Compound

ABSTRACT

There is provided a compound of Formula I wherein R3, R4, R5, R6 and R7 are independently selected from H and —Y—R8; wherein each R8 is independently selected from —OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO2), H-bond acceptors, and halogens; wherein at least one of R3, R4, R5, R6 and R7 is —Y—R8 wherein R8 is selected from substituted and unsubstituted heterocyclic rings and amino substituted phenyl groups, wherein X is a bond or a linker group; wherein Y is an optional linker group; and wherein ring A is optionally further substituted; wherein R9 is selected from H, —OH and —OSO2NR1R2; wherein R1 and R2 are independently selected from H and hydrocarbyl; wherein (a) X is a bond and at least one of R3, R4, R5, R6 and R7 is —Y—R8; OR (b) R9 is —OSO2NR1R2 or —OH and four of R3, R4, R5, R6 and R7 are H and one of R3, R4, R5, R6 and R7 is —Y—R8.

INCORPORATION BY REFERENCE

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/139,237 filed 13-JUN-2008 now U.S. Pat. No. 8,022,224, whichis a continuation in part of International Patent Application Serial No.PCT/GB2006/004630 filed Dec. 12, 2006 and published as WO 2007/068905 onJun. 21, 2007, which claims priority from GB Application No. 0525323.2filed Dec. 13, 2005.

Each of the above referenced applications, and each document cited inthis text (“application cited documents”) and each document cited orreferenced in each of the application cited documents, and anymanufacturer's specifications or instructions for any products mentionedin this text and in any document incorporated into this text, are herebyincorporated herein by reference; and, technology in each of thedocuments incorporated herein by reference can be used in the practiceof this invention.

FIELD OF INVENTION

The present invention relates to a compound.

In particular the present invention relates to a compound and to apharmaceutical composition comprising the compound. The presentinvention also relates to the use of the compound or composition intherapy applications.

BACKGROUND TO THE INVENTION

Evidence suggests that oestrogens are the major mitogens involved inpromoting the growth of tumours in endocrine-dependent tissues, such asthe breast and endometrium. normal breast tissue or blood. In situsynthesis of oestrogen is thought to make an important contribution tothe high levels of oestrogens in tumours and therefore inhibitors, inparticular specific inhibitors, of oestrogen biosynthesis are ofpotential value for the treatment of endocrine-dependent tumours.

Over the past two decades, there has been considerable interest in thedevelopment of inhibitors of the aromatase pathway—which converts theandrogen precursor androstenedione to oestrone. However, there is nowevidence that the oestrone sulphatase (E1-STS) pathway, i.e. thehydrolysis of oestrone sulphate to oestrone (E1S to E1), and aromatase(i.e. conversion of androstenedione to oestrone) account for theproduction of oestrogens in breast tumours.

FIGS. 1 and 2 are schematic diagrams showing some of the enzymesinvolved in the in situ synthesis of oestrone from oestrone sulphate,oestradiol and androstenedione.

In FIG. 2, which schematically shows the origin of oestrogenic steroidsin postmenopausal women, “ER″ denotes Oestrogen Receptor, “DHEA-S”denotes Dehydroepiandrosterone-Sulphate, “Adiol” denotes Androstenediol,“E1 —STS” denotes Oestrone Sulphatase, “DHEA-STS” denotesDHEA-sulphatase, “Adiol-STS” denotes Adiol Sulphatase, and “17B-HSD”denotes Oestradiol 17B-hydroxysteroid dehydrogenase.

As can be seen, the main two enzymes that are involved in the peripheralsynthesis of oestrogens are the aromatase enzyme and the enzyme oestronesulphatase.

In short, the aromatase enzyme converts androstenedione, which issecreted in large amounts by the adrenal cortex, to oestrone. Recentreports have suggested that some flavones could inhibit aromataseactivity.

Much of the oestrone so formed, however, is converted to oestronesulphate (E1S) and there is now a considerable body of evidence showingthat E1S in plasma and tissue acts as a reservoir for the formation ofoestrone by the action of oestrone sulphatase.

In this regard, it is now believed that the oestrone sulphatase (E1-STS)pathway—i.e. the hydrolysis of oestrone sulphate to oestrone (E1S to E1)is a major source of oestrogen in breast tumours. This theory issupported by a modest reduction of plasma oestrogen concentration inpostmenopausal women with breast cancer treated by aromatase inhibitors,such as aminoglutethimide and 4-hydroxyandrostenedione and also by thefact that plasma E1S concentration in these aromatase inhibitor-treatedpatients remains relatively high. The long half-life of E1S in blood(10-12 h) compared with the unconjugated oestrogens (20 min) and highlevels of steroid sulphatase activity in liver and, normal and malignantbreast tissues, also lend support to this theory.

Thus, oestrogen formation in malignant breast and endometrial tissuesvia the sulphatase pathway makes a major contribution to the highconcentration of oestrogens which are present in these tumours. However,inhibition of both the aromatase and sulphatase pathways could offerconsiderable therapeutic benefit.

PCT/GB92/01587 teaches novel steroid sulphatase inhibitors andpharmaceutical compositions containing them for use in the treatment ofoestrone dependent tumours, especially breast cancer. These steroidsulphatase inhibitors are sulphamate esters, such as N,N-dimethyloestrone-3-sulphamate and, preferably, oestrone-3-sulphamate (otherwiseknown as “EMATE”). EMATE has the following structure:

It is known that EMATE is a potent E1-STS inhibitor as it displays morethan 99% inhibition of E1-STS activity in intact MCF-7 cells at 0.1 nM.EMATE also inhibits the E1-STS enzyme in a time- andconcentration-dependent manner, indicating that it acts as an activesite-directed inactivator. Although EMATE was originally designed forthe inhibition of E1-STS, it also inhibits dehydroepiandrosteronesulphatase (DHEA-STS), which is an enzyme that is believed to have apivotal role in regulating the biosynthesis of the oestrogenic steroidandrostenediol. Also, there is now evidence to suggest thatandrostenediol may be of even greater importance as a promoter of breasttumour growth. EMATE is also active in vivo as almost completeinhibition of rat liver E1-STS (99%) and DHEA-STS (99%) activitiesresulted when it is administered either orally or subcutaneously. Inaddition, EMATE has been shown to have a memory enhancing effect inrats. Studies in mice have suggested an association between DHEA-STSactivity and the regulation of part of the immune response. It isthought that this may also occur in humans. The bridging O-atom of thesulphamate moiety in EMATE is important for inhibitory activity. Thus,when the 3-O-atom is replaced by other heteroatoms as inoestrone-3-N-sulphamate and oestrone-3-S-sulphamate, these analogues areweaker non-time-dependent inactivators.

In addition to oestrone, the other major steroid with oestrogenicproperties which is produced by postmenopausal women is androstenediol(see FIG. 2).

Androstenediol, although an androgen, can bind to the oestrogen receptor(ER) and can stimulate the growth of ER positive breast cancer cells andthe growth of carcinogen-induced mammary tumours in the rat.Importantly, in postmenopausal women 90% of the androstenediol producedoriginates from the androgen dehydroepiandrosterone sulphate (DHEA-S)which is secreted in large amounts by the adrenal cortex. DHEA-S isconverted to DHEA by DHEA sulphatase, which may be the same as, ordifferent from, the enzyme, oestrone sulphatase, which is responsiblefor the hydrolysis of E1S.

During the last 10-15 years considerable research has also been carriedout to develop potent aromatase inhibitors, some of which are nowmarketed. However, in three recent reports of postmenopausal women withbreast cancer who received aromatase inhibitor therapy, plasma E1Sconcentrations remained between 400-1000 pg/ml.

In summation therefore in situ synthesis of oestrogen is thought to makean important contribution to the high levels of oestrogens in tumoursand therefore specific inhibitors of oestrogen biosynthesis are ofpotential value for the treatment of endocrine-dependent tumours.

Moreover, even though oestrogen formation in malignant breast andendometrial tissues via the sulphatase pathway makes a majorcontribution to the high concentration of oestrogens, there are stillother enzymatic pathways that contribute to in vivo synthesis ofoestrogen.

Applicants' earlier application WO03/045925 teaches compounds which mayact as inhibitors of both aromatase and sulphatase. Many of thecompounds of the disclosure are found to be extremely potent inhibitorsof both of these enzymes. However, there is a desire to providealternative compounds or improved compounds.

The present invention seeks to provide novel compounds suitable for theinhibition of steroid sulphatase activity and aromatase activity.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY ASPECTS OF THE PRESENT INVENTION

The present invention is based on the surprising finding that certainpolycyclic compounds could be used as effective steroid sulphataseinhibitors and/or aromatase inhibitors and/or as agents that caninfluence cell cycling and/or as agents that can influence apoptosis.

Accordingly, it is an object of the invention to not encompass withinthe invention any previously known product, process of making theproduct, or method of using the product such that Applicants reserve theright and hereby disclose a disclaimer of any previously known product,process, or method. It is further noted that the invention does notintend to encompass within the scope of the invention any product,process, or making of the product or method of using the product, whichdoes not meet the written description and enablement requirements of theUSPTO (35 U.S.C. §112, first paragraph) or the EPO (Article 83 of theEPC), such that Applicants reserve the right and hereby disclose adisclaimer of any previously described product, process of making theproduct, or method of using the product. It is noted that in thisdisclosure and particularly in the claims and/or paragraphs, terms suchas “comprises”, “comprised”, “comprising” and the like can have themeaning attributed to it in U.S. patent law; e.g., they can mean“includes”, “included”, “including”, and the like; and that terms suchas “consisting essentially of” and “consists essentially of” have themeaning ascribed to them in U.S. patent law, e.g., they allow forelements not explicitly recited, but exclude elements that are found inthe prior art or that affect a basic or novel characteristic of theinvention. These and other embodiments are disclosed or are obvious fromand encompassed by, the following Detailed Description.

DETAILED ASPECTS OF THE PRESENT INVENTION

According to one aspect of the present invention, there is provided acompound of Formula I

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

The term “hydrocarbyl group” as used herein means a group comprising atleast C and H and may optionally comprise one or more other suitablesubstituents. Examples of such substituents may include halo, alkoxy,nitro, an alkyl group, a cyclic group etc. In addition to thepossibility of the substituents being a cyclic group, a combination ofsubstituents may form a cyclic group. If the hydrocarbyl group comprisesmore than one C then those carbons need not necessarily be linked toeach other. For example, at least two of the carbons may be linked via asuitable element or group. Thus, the hydrocarbyl group may containhetero atoms. Suitable hetero atoms will be apparent to those skilled inthe art and include, for instance, sulphur, nitrogen and oxygen. Anon-limiting example of a hydrocarbyl group is an acyl group.

The term “oxyhydrocarbyl” group as used herein means a group comprisingat least C, H and O and may optionally comprise one or more othersuitable substituents. Examples of such substituents may include halo-,alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to thepossibility of the substituents being a cyclic group, a combination ofsubstituents may form a cyclic group. If the oxyhydrocarbyl groupcomprises more than one C then those carbons need not necessarily belinked to each other. For example, at least two of the carbons may belinked via a suitable element or group. Thus, the oxyhydrocarbyl groupmay contain hetero atoms. Suitable hetero atoms will be apparent tothose skilled in the art and include, for instance, sulphur andnitrogen.

According to one aspect of the present invention, there is provided amethod comprising (a) performing a steroid sulphatase (STS) assay and/oraromatase assay with one or more candidate compounds defined herein; (b)determining whether one or more of said candidate compounds is/arecapable of modulating STS activity and/or aromatase activity and/or cellcycling and/or cell growth and/or apoptosis; and (c) selecting one ormore of said candidate compounds that is/are capable of modulating STSactivity and/or aromatase activity and/or cell cycling and/or cellgrowth and/or apoptosis.

According to one aspect of the present invention, there is provided amethod comprising (a) performing a steroid sulphatase assay and/oraromatase assay with one or more candidate compounds as defined herein;(b) determining whether one or more of said candidate compounds is/arecapable of inhibiting STS and/or aromatase activity; and (c) selectingone or more of said candidate compounds that is/are capable ofinhibiting STS activity and/or aromatase activity and/or cell cyclingand/or cell growth and/or apoptosis.

In any one of the methods of the present invention, one or moreadditional steps may be present. For example, the method may alsoinclude the step of modifying the identified candidate compound (such asby chemical and/or enzymatic techniques) and the optional additionalstep of testing that modified compound for STS inhibition effects (whichmay be to see if the effect is greater or different) and/or aromataseinhibition effects (which may be to see if the effect is greater ordifferent). By way of further example, the method may also include thestep of determining the structure (such as by use of crystallographictechniques) of the identified candidate compound and then performingcomputer modelling studies—such as to further increase its STS and/oraromatase inhibitory action. Thus, the present invention alsoencompasses a computer having a dataset (such as the crystallographicco-ordinates) for said identified candidate compound. The presentinvention also encompasses that identified candidate compound whenpresented on a computer screen for the analysis thereof—such as enzymeand/or protein binding studies.

According to one aspect of the present invention, there is provided acompound identified by the method of the present invention.

According to one aspect of the present invention, there is provided acompound according to the present invention for use in medicine.

According to one aspect of the present invention, there is provided apharmaceutical composition comprising the compound according to thepresent invention optionally admixed with a pharmaceutically acceptablecarrier, diluent, excipient or adjuvant.

According to one aspect of the present invention, there is provided theuse of a compound according to the present invention in the manufactureof a medicament for use in the therapy of a condition or diseaseassociated with STS and/or aromatase and/or cell cycling and/orapoptosis and/or cell growth.

According to one aspect of the present invention, there is provided theuse of a compound according to the present invention in the manufactureof a medicament for use in the therapy of a condition or diseaseassociated with adverse STS levels and/or adverse aromatase levelsand/or cell cycling and/or apoptosis and/or cell growth.

According to one aspect of the present invention, there is provided theuse of a compound according to the present invention in the manufactureof a medicament for inhibiting STS activity and/or inhibiting aromataseactivity.

According to one aspect of the present invention, there is provided theuse of a compound according to the present invention in the manufactureof a medicament for inhibiting STS activity and inhibiting aromataseactivity.

The present invention also encompasses the novel compounds of thepresent invention (such as those presented herein), as well as processesfor making same (such as the processes presented herein) as well asnovel intermediates (such as those presented herein) for use in thoseprocesses.

The compounds of the present invention may comprise other substituents.These other substituents may, for example, further increase the activityof the compounds of the present invention and/or increase stability (exvivo and/or in vivo).

For ease of reference, these and further aspects of the presentinvention are now discussed under appropriate section headings. However,the teachings under each section are not necessarily limited to eachparticular section.

Some Advantages

One key advantage of the present invention is that the compounds of thepresent invention can act as aromatase inhibitors.

One key advantage of the present invention is that the compounds of thepresent invention can act as STS inhibitors.

One key advantage of the present invention is that the compounds of thepresent invention can act as STS inhibitors and aromatase inhibitors.

Another advantage of the compounds of the present invention is that theymay be potent in vivo.

Some of the compounds of the present invention may be non-oestrogeniccompounds. Here, the term “non-oestrogenic” means exhibiting no orsubstantially no oestrogenic activity. Here, by the term“non-oestrogenic” means exhibiting no or substantially no systemicoestrogenic activity, such as that determined by Protocol 4.

Another advantage is that some of the compounds may not be capable ofbeing metabolised to compounds which display or induce hormonalactivity.

Some of the compounds of the present invention are also advantageous inthat they may be orally active.

Some of the compounds of the present invention may useful for theprevention and/or treatment of cancer, such as breast cancer, as well as(or in the alternative) non-malignant conditions, such as the preventionand/or treatment of inflammatory conditions—such as conditionsassociated with any one or more of: autoimmunity, including for example,rheumatoid arthritis, type I and II diabetes, systemic lupuserythematosus, multiple sclerosis, myasthenia gravis, thyroiditis,vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g.acne, psoriasis and contact dermatitis; graft versus host disease;eczema; asthma and organ rejection following transplantation. Thecompounds of the present invention are useful particularly whenpharmaceuticals may need to be administered from an early age.

Thus, some of the compounds of the present invention are also believedto have therapeutic uses other than for the treatment ofendocrine-dependent cancers, such as the treatment of autoimmunediseases.

The compounds of the present invention may also be useful as an inducerof apoptosis.

The compounds of the present invention may also be useful as a cellgrowth inhibitors.

Preferable Aspects

Hydrocarbyl Group

A typical hydrocarbyl group is a hydrocarbon group. Here the term“hydrocarbon” means any one of an alkyl group, an alkenyl group, analkynyl group, which groups may be linear, branched or cyclic, or anaryl group. The term hydrocarbon also includes those groups but whereinthey have been optionally substituted. If the hydrocarbon is a branchedstructure having substituent(s) thereon, then the substitution may be oneither the hydrocarbon backbone or on the branch; alternatively thesubstitutions may be on the hydrocarbon backbone and on the branch.

The hydrocarbyl/hydrocarbon/alkyl may be straight chain or branchedand/or may be saturated or unsaturated.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may beselected from straight or branched hydrocarbon groups containing atleast one hetero atom in the group.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may be ahydrocarbyl group comprising at least two carbons or wherein the totalnumber of carbons and hetero atoms is at least two.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may beselected from hydrocarbyl groups containing at least one hetero atom inthe group. Preferably the hetero atom is selected from sulphur, nitrogenand oxygen.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may beselected from straight or branched hydrocarbon groups containing atleast one hetero atom in the group. Preferably the hetero atom isselected from sulphur, nitrogen and oxygen.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may beselected from straight or branched alkyl groups, preferably C₁₋₁₀ alkyl,more preferably C₁₋₅ alkyl, containing at least one hetero atom in thegroup. Preferably the hetero atom is selected from sulphur, nitrogen andoxygen.

In one preferred aspect the hydrocarbyl/hydrocarbon/alkyl may beselected from straight chain alkyl groups, preferably C₁₋₁₀ alkyl, morepreferably C₁₋₅ alkyl, containing at least one hetero atom in the group.Preferably the hetero atom is selected from sulphur, nitrogen andoxygen.

The hydrocarbyl/hydrocarbon/alkyl may be selected from

-   -   C₁-C₁₀ hydrocarbyl,    -   C₁-C₅ hydrocarbyl    -   C₁-C₃ hydrocarbyl.    -   hydrocarbon groups    -   C₁-C₁₀ hydrocarbon    -   C₁-C₅ hydrocarbon    -   C₁-C₃ hydrocarbon.    -   alkyl groups    -   C₁-C₁₀ alkyl    -   C₁-C₅ alkyl    -   C₁-C₃ alkyl.

The hydrocarbyl/hydrocarbon/alkyl may be straight chain or branchedand/or may be saturated or unsaturated.

The hydrocarbyl/hydrocarbon/alkyl may be straight or branchedhydrocarbon groups containing at least one hetero atom in the group.

Oxyhydrocarbyl Group

In one embodiment of the present invention, the oxyhydrocarbyl group isa oxyhydrocarbon group.

Here the term “oxyhydrocarbon” means any one of an alkoxy group, anoxyalkenyl group, an oxyalkynyl group, which groups may be linear,branched or cyclic, or an oxyaryl group. The term oxyhydrocarbon alsoincludes those groups but wherein they have been optionally substituted.If the oxyhydrocarbon is a branched structure having substituent(s)thereon, then the substitution may be on either the hydrocarbon backboneor on the branch; alternatively the substitutions may be on thehydrocarbon backbone and on the branch.

Each of the above teachings in respect of hydrocarbyl groups equallyapplies to the analogous oxyhydrocarbyl groups, that is thecorresponding oxyhydrocarbyl group which comprises an oxygen in additionto the hydrocarbyl.

Typically, the oxyhydrocarbyl group is of the formula C₁₋₆O (such as aC₁₋₃O).

Compound

According to one aspect of the present invention, there is provided acompound of Formula I

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaII

wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉ is—OSO₂NR₁R₂), and wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈and at least one of R₃, R₄, R₅, R₆ and R₇ is or comprises a groupsselected from cyano (—CN), nitro (—NO₂), H-bond acceptors, and halogens.

In a further aspect the present invention provides a compound of FormulaII

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein four of R₃, R₄, R₅, R₆ and R₇ are H and one of R₃, R₄, R₅,    R₆ and R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaIII

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaMa

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaIV

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaIVa

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaV

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaVa

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), intro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂ (in one aspect R₉    is —OSO₂NR₁R₂)-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

In a further aspect the present invention provides a compound of FormulaVI

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is    selected from substituted and unsubstituted heterocyclic rings and    amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally substituted-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In this aspect R₃ is —Y—R₈ and/or R₄ is —Y—R₈ and/or R₅ is —Y—R₈ and/orR₆ is —Y—R₈ and/or R₇ is —Y—R₈.

X

As discussed herein linker X is a linker group or is a bond. In oneaspect X is a linker group. In one aspect X is a bond. It will beappreciated by one skilled in the art that when X is a bond the presentinvention provides a compound of the formula

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R_(S)    is selected from substituted and unsubstituted heterocyclic rings    and amino substituted phenyl groups,-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

The aspect wherein X is a bond is applicable to each of the preferredaspects described herein for example the aspect shown in preferredFormulae II to VI.

Preferably X is selected from, or when X is a linker it is selectedfrom, a bond, hydrocarbyl, oxyhydrocarbyl, thiohydrocarbyl, COO, CO, S,O, SO, SO₂, NR, and SO₂NR, wherein R is selected from H and hydrocarbylgroups.

Preferably X is selected from hydrocarbyl, oxyhydrocarbyl,thiohydrocarbyl, COO, CO, S, O, SO, SO₂, NR, and SO₂NR, wherein R isselected from H and hydrocarbyl groups.

Preferably X is selected from —CH₂—S—, —C≡C—, —CH₂—O—, —O—, and—CH₂CH₂—.

The term “thiohydrocarbyl group” as used herein means a group comprisingat least S, C and H and may optionally comprise one or more othersuitable substituents. Examples of such substituents may include halo,alkoxy, nitro, an alkyl group, a cyclic group etc. In addition to thepossibility of the substituents being a cyclic group, a combination ofsubstituents may form a cyclic group. If the hydrocarbyl group comprisesmore than one C then those carbons need not necessarily be linked toeach other. For example, at least two of the carbons may be linked via asuitable element or group. Thus, the thiohydrocarbyl group may containhetero atoms. Suitable hetero atoms will be apparent to those skilled inthe art and include, for instance, nitrogen and oxygen.

When X is a hydrocarbyl group or in the option that X may be ahydrocarbyl group, preferably the hydrocarbyl group is a straight ofbranched alkyl group.

When X is a hydrocarbyl group or in the option that X may be ahydrocarbyl group, preferably the hydrocarbyl group is a straight chainalkyl group.

When X is a oxyhydrocarbyl group or in the option that X may be aoxyhydrocarbyl group, preferably the oxyhydrocarbyl group is —O-alkyl-,wherein alkyl is a straight of branched alkyl group.

When X is a oxyhydrocarbyl group or in the option that X may be aoxyhydrocarbyl group, preferably the oxyhydrocarbyl group is —O-alkyl-,wherein alkyl is a straight chain alkyl group

In one preferred aspect X is selected from groups selected from —O—,—C≡C—, (CH₂)n, CH═CH (preferably trans configuration), O(CH₂)n, (CH₂)nO,S(CH₂)n, (CH₂)nS, CO(CH₂)n, (CH₂)nCO, CONH(CH₂)n, (CH₂)nCONH, COO(CH₂)n,(CH₂)nCOO, SO(CH₂)n, (CH₂)nSO, SO₂(CH₂)n, (CH₂)nSO₂, SO₂NC₁₋₆alkyl(CH₂)n (such as SO₂NMe(CH₂)n), (CH₂)nSO₂NC₁₋₆alkyl (such as(CH₂)nSO₂NMe); SO₂NH(CH₂)n, and (CH₂)nSO₂NH; wherein n is independentlyan integer from 0 to 6. Preferably n is independently an integer from 1to 6, more preferably from 1 to 3, such as 1, 2 or 3.

In one preferred aspect X is selected from groups selected from —O—,—C≡C—, CH₂)n, O(CH₂)n, (CH₂)nO, S(CH₂)n, (CH₂)nS, CO(CH₂)n, (CH₂)nCO,CONH(CH₂)n, (CH₂)nCONH, COO(CH₂)n, (CH₂)nCOO, SO(CH₂)n, (CH₂)nSO,SO₂(CH₂)n, (CH₂)nSO₂, SO₂NH(CH₂)n, and (CH₂)nSO₂NH; wherein n isindependently an integer from 0 to 6. Preferably n is independently aninteger from 1 to 6, more preferably from 1 to 3, such as 1, 2 or 3.

In one preferred aspect X is selected from groups selected from —O—,—C≡C—, OCH₂, and SCH₂.

Y

In one preferred aspect Y is selected from hydrocarbyl, oxyhydrocarbyl,COO, CO, S, O, SO, SO₂, NR, and SO₂NR, wherein R is selected from H andhydrocarbyl groups.

In one preferred aspect Y is selected from hydrocarbyl, CO, and SO₂,

When Y is a hydrocarbyl group or in the option that Y may be ahydrocarbyl group, preferably the hydrocarbyl group is a straight ofbranched alkyl group.

When Y is a hydrocarbyl group or in the option that Y may be ahydrocarbyl group, preferably the hydrocarbyl group is a straight chainalkyl group.

In one preferred aspect Y is selected from groups selected fromC_(m)H_(2m) such as (CH₂)m, CO(CH₂)m, (CH₂)_(m)CO, SO₂(CH₂)m and whereinm is independently an integer from 0 to 6. Preferably m is independentlyan integer from 1 to 6, more preferably from 1 to 3, such as 1, 2 or 3.

In a highly preferred aspect Y is C_(m)H_(2m) such as (CH₂)m, wherein mis an integer from 0 to 6, preferably an integer from 1 to 6, morepreferably from 1 to 3, such as 1, 2 or 3. In a highly preferred aspectY is —CH₂— or —C(CH₃)₂—.

R8

R₈ may be selected from any suitable substituents. For example R₈ may beselected from hydrocarbyl, oxyhydrocarbyl, thiohydrocarbyl, halogens,—CN, COO, CO, S, O, SO, SO₂, NR, and SO₂NR, wherein R is selected from Hand hydrocarbyl groups. However at least one R₈ is selected fromsubstituted and unsubstituted heterocyclic rings and amino substitutedphenyl groups.

Preferably at least one R₈ is selected from or each R₈ is selected fromhydrocarbyl, oxyhydrocarbyl, halogens, and —CN.

In respect of R₈, preferred hydrocarbyl and oxyhydrocarbyl are cyclicgroups.

R₈ need not be a cyclic structure. In this regard, R₈ may be a linearstructure that may have the ability to conform to a ring like structurewhen in in vivo. However in preferred aspects R₈ is a cyclic structure.

R₈ may be a heterocyclic group (a heterocycle) or a non-heterocyclicgroup. Suitable hetero atoms of a heterocyclic group include N, S and O.Preferably R₈ is a heterocyclic group wherein the ring comprises carbonand nitrogen.

When hetero atoms are present in a ring system to provide a heterocyclicgroup, the hetero atoms may be present in any amount. In one preferredaspect R₈ is a ring system comprising carbon and one or more heteroatoms selected from N, S and O.

R₈ may be is a saturated ring structure or an unsaturated ring structure(such as an aryl group).

Preferably, R₈ is an aryl ring.

In one aspect of the invention at least one R₈ is selected from or eachR₈ is selected from substituted or unsubstituted aromatic rings.

In one aspect at least one R₈ is selected from or each R₈ is selectedfrom polycyclic groups, which need not be a fused polycycle. The term“polycyclic” includes fused and non-fused ring structures includingcombinations thereof. If the ring system of R₈ is polycyclic some or allof the ring components of the ring system may be fused together orjoined via one or more suitable spacer groups.

The ring size of R₈ may be chosen by one skilled in the art to achievecompounds having desired activity. Typically R₈ is a ring systemcomprising from 3 to 10 members, such as ring systems comprising from 5,6 or 7 members.

Heterocyclic ring systems for use in the present invention includeimidazole, tetrazole, pyrazole, triazole, such as 1H-1,2,3-triazole,1H-1,2,4-triazole, 4H-1,2,4-triazole; optionally substituted 5- or6-membered heterocyclic group containing 1 to 3 hetero atoms eachselected from N, O and S, optionally substituted aryl (monocyclic orpolycyclic aromatic), pyridazine, pyrimidine, pyridine, triazine such as1,3,5 triazine, and optionally substituted bicyclic condensedheterocyclic group consisting of the above heterocyclic group condensedwith benzene.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from ring systems described herein, halogens, and —CN.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from —CN, halogens and ring systems comprising carbon and one,two or three hetero atoms.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from —CN, halogens and ring systems comprising carbon and oneor more hetero atoms selected from Nitrogen, Sulphur and Oxygen.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from —CN, halogens and heterocyclic ring systems, wherein thering comprises carbon and nitrogen.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from cyano (—CN), halogens and 4H-1,2,4-triazole,1H-1,2,4-triazole and 1H-1,2,3-triazole.

In one preferred aspect at least one R₈ is selected from or each R₈ isselected from 4H-1,2,4-triazole, 1H-1,2,4-triazole and1H-1,2,3-triazole.

In one preferred aspect at least one R₈ is or each R₈ is1H-1,2,4-triazole.

In a highly preferred aspect at least one R₈ is or each R₈ is

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicrings.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted ring systemscomprising carbon and one, two or three hetero atoms.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted ring systemscomprising carbon and one or more hetero atoms selected from Nitrogen,Sulphur and Oxygen.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicring systems, wherein the ring comprises carbon and nitrogen.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicring systems comprising from 3 to 10 members.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicring systems comprising from 5, 6 or 7 members.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from 4H-1,2,4-triazole, 1H-1,2,4-triazole and1H-1,2,3-triazole.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is 1H-1,2,4-triazole.

In one preferred aspect at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein —Y—R₈ is —CH₂-1H-1,2,4-triazole.

Thus according to one highly preferred aspect of the present invention,there is provided a compound of Formula I

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein    R₈₁H-1,2,4-triazole;-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

In one aspect R₈ may an amino substituted phenyl group. It will beunderstood by one skilled in the art that a typical amino substitutedphenyl group is of the formula

wherein R₁₀ and R₁₁ are independently selected from H and hydrocarbyl.

A preferred amino substituted phenyl group is of the formula

wherein R₁₀ and R₁₁ are independently selected from H and hydrocarbyl.

In one preferred aspect R₁₀ and R₁₁ are independently selected from H,alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, ortogether represent alkylene, wherein the or each alkyl or cycloalkyl oralkenyl or optionally contain one or more hetero atoms or groups. Whensubstituted, the amino phenyl groups may contain one or two N-alkyl,N-alkenyl, N-cycloalkyl or N-aryl substituents, preferably containing oreach containing a maximum of 10 carbon atoms.

When R₁₀ and/or R₁₁ is hydrocarbyl, the preferred values are those whereR₁ and R₂ are each independently selected C₁-C₁₀ hydrocarbyl, C₁-C₅hydrocarbyl, C₁-C₃ hydrocarbyl, C₁-C₁₀ hydrocarbon, C₁-C₅ hydrocarbon,C₁-C₃ hydrocarbon, C₁-C₁₀ alkyl, C₁-C₅ alkyl and C₁-C₃ alkyl.

When R₁₀ and/or R₁₁ is alkyl, the preferred values are those where R₁₀and R₁₁ are each independently selected from lower alkyl groupscontaining from 1 to 6 carbon atoms, that is to say methyl, ethyl,propyl etc. R₁₀ and R₁₁ may both be methyl.

When R₁₀ and/or R₁₁ is aryl, typical values are phenyl and tolyl(PhCH₃).

Where R₁₀ and/or R₁₁ represent cycloalkyl, typical values arecyclopropyl, cyclopentyl, cyclohexyl etc.

When joined together R₁₀ and R₁₁ typically represent an alkylene groupproviding a chain of 4 to 6 carbon atoms, optionally interrupted by oneor more hetero atoms or groups, e.g. to provide a 5 memberedheterocycle, e.g. morpholino, pyrrolidino or piperidino.

In some preferred embodiments, at least one of R₁₀ and R₁₁ is H.

In some further preferred embodiments, each of R₁₀ and R₁₁ is H.

R₈ may be substituted by one or more substituents. Typical substituentsinclude hydrocarbyl, oxyhydrocarbyl, halo and cyano (—C□N) groups. R₈may also be substituted by one or more substituents selected fromphosphonate groups, thiophosphonate groups, sulphonate groups andsulphonamide groups.

In one preferred aspect R₈ is unsubstituted.

—Y—R8

In one preferred aspect at least one or each —Y—R₈ is selected—CH₂-1H-1,2,4-triazole, —CN, —C(CH₃)₂—CN, and —F.

In a highly preferred for at least one or each —Y—R₈, Y is —CH₂— and R8is

Thus in this aspect for at least one or each —Y—R₈, —Y—R₈ together arethe group

In a highly preferred aspect for at least one or each —Y—R₈, Y is notpresent and R₈ is —CN. Thus in this aspect for at least one or each—Y—R₈, —Y—R8 together are the group —CN.

In a highly preferred aspect for at least one or each —Y—R8, Y is—C(CH₃)₂— and R₈ is —CN. Thus in this aspect —Y—R8 together are thegroup —C(CH₃)₂—CN.

In a highly preferred aspect for at least one or each —Y—R₈, Y is notpresent and R8 is —F. Thus in this aspect for at least one or each—Y—R₈, —Y—R8 together are the group —F.

In a highly preferred at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein Y is —CH₂— and R₈ is

Thus in this aspect at least one of R₃, R₄, R₅, R₆ and R₇ is the group

R9

As discussed herein R₉ is selected from H, —OH and —OSO₂NR₁R₂

In a preferred aspect R₉ is selected from —OH and —OSO₂NR₁R₂

In one aspect R₉ is H.

In a preferred aspect R₉ is —OH. Applicants have found that the presenceof the —OH may enhance the aromatase inhibitory activity of compounds ofthe present invention. In this respect the presence of this group isadvantageous.

In a preferred aspect R₉ is —OSO₂NR₁R₂. Applicants have found that thepresence of the —OSO₂NR₁R₂ group provide steroid sulphatase inhibitoryactivity. In this respect the presence of this group is advantageous.

R1 & R2

In one preferred aspect R₁ and R₂ are independently selected from H,alkyl, cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, ortogether represent alkylene, wherein the or each alkyl or cycloalkyl oralkenyl or optionally contain one or more hetero atoms or groups.

In one preferred aspect at least one of R₁ and R₂ is H.

In one preferred aspect R₁ is H and R₂ is H.

Ring A

As noted herein the compounds of the present invention may compriseother substituents. These other substituents may, for example, furtherincrease the activity of the compounds of the present invention and/orincrease stability (ex vivo and/or in vivo). For example the ringdenoted A and B in the general formulae may comprise other substituents.However in one preferred aspect rings A and B are independently notfurther substituted.

In one aspect ring A is further substituted.

If ring A is further substituted, the further substitution may be bygroups selected from

-   -   —OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (—CN),        nitro (—NO₂), H-bond acceptors, and halogens.    -   C1-6 alkyl groups, C1-6 alkoxy groups, cyano (—CN), nitro (—NO₂)        and halogens.    -   CH₃, —CH₂CH₃, —OCH₃, cyano (—CN), nitro (—NO₂) and halogens.

If ring A is further substituted the substituent may be attached to ringA at more than one point such that ring A and the substituent providefused rings which form a polycyclic structure. For example ring Atogether with the optional further substituents may form a substitutedor unsubstituted naphthalene ring or may form a substituted orunsubstituted dibenzofuranyl ring. Preferred substituents of the fusedsystems and in particular the naphthalene ring are —O-alkyl such as —OMeand —OH

If ring A is further substituted, the further substitution is preferablya halogen and in particular, Cl, Br and/or F.

If ring A is further substituted, preferably ring A is substitution byonly one further substituent, that is preferably a halogen and inparticular, Cl, Br and/or F.

If ring A is substituted, preferably ring A is substituted by only oneor two groups.

In a preferred aspect ring is A is optionally further substituted bygroups selected —Cl, —OH, fused phenyl, phenyl, —OMe, —OCH₂Ph, —CN,—C(O)-Ph, —F, —O-Ph, —C(O)-Me, fused phenyl optional substituted withone of —OMe or —OH, and a fused heterocyclic group such that ring Aforms a dibenzofuranyl.

In a preferred aspect ring A together with any optional substituents isselected from:

If R₉ is a sulphamate group and ring A is further substituted,preferably the further substituent is at a position on the ring ortho tothe sulphamate group.

R3 to R7

As discussed herein R₃, R₄, R₅, R₆ and R₇ are independently selectedfrom H and —Y—R₈, wherein each R₈ is independently selected from —OH,hydrocarbyl groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂),H-bond acceptors, and halogens; with the proviso that (a) X is a bondand at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ isselected from substituted and unsubstituted heterocyclic rings and aminosubstituted phenyl groups; OR (b) R₉ is —OSO₂NR₁R₂ or —OH and four ofR₃, R₄, R₅, R₆ and R₇ are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicrings and amino substituted phenyl groups.

In one aspect X is a bond and at least R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.(wherein R₈ is selected from substituted and unsubstituted heterocyclicrings and amino substituted phenyl groups).

In this aspect preferably at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from substituted and unsubstituted heterocyclicrings and amino substituted phenyl groups, and at least one of R₃, R₄,R₅, R₆ and R₇ is a —CN group.

In one aspect R₉ is —OSO₂NR₁R₂ and four of R₃, R₄, R₅, R₆ and R₇ are Hand one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈. In this aspect it is possiblethat

-   -   R₃, R₄, R₆ and R₇ are H and R₅ is —Y—R₈ (wherein R₈ is selected        from substituted and unsubstituted heterocyclic rings and amino        substituted phenyl groups),    -   R₃, R₅, R₆ and R₇ are H and R₄ is —Y—R₈. (or R₃, R₄, R₅ and R₇        are H and R₆ is —Y—R₈) (wherein R₈ is selected from substituted        and unsubstituted heterocyclic rings and amino substituted        phenyl groups),    -   R₄, R₅, R₆ and R₇ are H and R₃ is —Y—R₈ (or R₃, R₄, R₅ and R₆        are H and R₇ is —Y—R₈) (wherein R₈ is selected from substituted        and unsubstituted heterocyclic rings and amino substituted        phenyl groups),        Further Preferred Compounds

A preferred compound of the present invention is a compound selectedfrom compounds of the formulae

A preferred compound of the present invention is a compound selectedfrom compounds of the formulae

A preferred compound of the present invention is a compound selectedfrom compounds of the formulae

Other Aspects

For some applications, preferably the compounds have no, or a minimal,oestrogenic effect.

For some applications, preferably the compounds have an oestrogeniceffect.

For some applications, preferably the compounds have a reversibleaction.

For some applications, preferably the compounds have an irreversibleaction.

In one embodiment, the compounds of the present invention are useful forthe treatment of breast cancer.

In one embodiment, the compounds of the present invention are useful forthe inhibition of a Cyp450 enzyme.

In one embodiment, the compounds of the present invention are useful forthe inhibition of a Cyp17 enzyme.

In one embodiment, the compounds of the present invention are useful forthe treatment of prostate cancer.

In one embodiment, the compounds of the present invention are useful forthe inhibition of a Cyp11B2 enzyme.

In one embodiment, the compounds of the present invention are useful forthe treatment of congestive heart failure.

In one embodiment, the compounds of the present invention are useful forthe treatment of myocardial fybrosis.

The present invention also covers novel intermediates that are useful toprepare the compounds of the present invention and metabolites of thecompounds of the present invention. For example, the present inventioncovers novel alcohol precursors for the compounds. By way of furtherexample, the present invention covers bis protected precursors for thecompounds. Examples of each of these precursors are presented herein.The present invention also encompasses a process comprising each or bothof those precursors for the synthesis of the compounds of the presentinvention.

In one broad aspect, when R₉ is —OSO₂NR₁R₂ or —OH, each R₈ isindependently selected from —OH, hydrocarbyl groups, oxyhydrocarbylgroups, cyano (—CN), nitro (—NO₂), H-bond acceptors, and halogens. Thusin this aspect the present invention provides a compound of Formula I

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈ in which R₈ is selected from substituted and unsubstituted        heterocyclic rings and amino substituted phenyl groups, or    -   (b) R₉ is —OSO₂NR₁R₂ or —OH, and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₃.        Steroid Sulphatase

Steroid sulphatase—which is sometimes referred to as steroid sulphataseor steryl sulphatase or “STS” for short—hydrolyses several sulfatedsteroids, such as oestrone sulphate, dehydroepiandrosterone sulphate andcholesterol sulphate. STS has been allocated the enzyme number EC3.1.6.2.

STS has been cloned and expressed. For example see Stein et al (J. Biol.Chem. 264:13865-13872 (1989)) and Yen et al (Cell 49:443-454 (1987)).STS is an enzyme that has been implicated in a number of diseaseconditions.

By way of example, workers have found that a total deficiency in STSproduces ichthyosis. According to some workers, STS deficiency is fairlyprevalent in Japan. The same workers (Sakura et al, J Inherit Metab Dis1997 November; 20(6):807-10) have also reported that allergicdiseases—such as bronchial asthma, allergic rhinitis, or atopicdermatitis—may be associated with a steroid sulphatase deficiency.

In addition to disease states being brought on through a total lack ofSTS activity, an increased level of STS activity may also bring aboutdisease conditions. By way of example, and as indicated above, there isstrong evidence to support a role of STS in breast cancer growth andmetastasis.

STS has also been implicated in other disease conditions. By way ofexample, Le Roy et al (Behav Genet. 1999 March; 29(2):131-6) havedetermined that there may be a genetic correlation between steroidsulphatase concentration and initiation of attack behaviour in mice. Theauthors conclude that sulphatation of steroids may be the prime mover ofa complex network, including genes shown to be implicated in aggressionby mutagenesis.

STS Inhibition

It is believed that some disease conditions associated with STS activityare due to conversion of a nonactive, sulphated oestrone to an active,nonsulphated oestrone. In disease conditions associated with STSactivity, it would be desirable to inhibit STS activity.

Here, the term “inhibit” includes reduce and/or eliminate and/or maskand/or prevent the detrimental action of STS.

STS Inhibitor

In accordance with the present invention, the compound of the presentinvention is capable of acting as an STS inhibitor.

Here, the term “inhibitor” as used herein with respect to the compoundof the present invention means a compound that can inhibit STSactivity—such as reduce and/or eliminate and/or mask and/or prevent thedetrimental action of STS. The STS inhibitor may act as an antagonist.

The ability of compounds to inhibit oestrone sulphatase activity can beassessed using either intact JEG3 choriocarcinoma cells or placentalmicrosomes. In addition, an animal model may be used. Details onsuitable Assay Protocols are presented in following sections. It is tobe noted that other assays could be used to determine STS activity andthus STS inhibition. For example, reference may also be made to theteachings of WO-A-99/50453.

In one aspect, for some applications, the compound is furthercharacterised by the feature that if the sulphamate group were to besubstituted by a sulphate group to form a sulphate derivative, then thesulphate derivative would be hydrolysable by an enzyme having steroidsulphatase (E.C. 3.1.6.2) activity—i.e. when incubated with steroidsulphatase EC 3.1.6.2 at pH 7.4 and 37° C.

In one preferred embodiment, if the sulphamate group of the compoundwere to be replaced with a sulphate group to form a sulphate compoundthen that sulphate compound would be hydrolysable by an enzyme havingsteroid sulphatase (E.C. 3.1.6.2) activity and would yield a Km value ofless than 200 mmolar, preferably less than 150 mmolar, preferably lessthan 100 mmolar, preferably less than 75 mmolar, preferably less than 50mmolar, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and37° C.

For some applications, preferably the compound of the present inventionhas at least about a 100 fold selectivity to a desired target (e.g. STSand/or aromatase), preferably at least about a 150 fold selectivity tothe desired target, preferably at least about a 200 fold selectivity tothe desired target, preferably at least about a 250 fold selectivity tothe desired target, preferably at least about a 300 fold selectivity tothe desired target, preferably at least about a 350 fold selectivity tothe desired target.

It is to be noted that the compound of the present invention may haveother beneficial properties in addition to or in the alternative to itsability to inhibit STS and/or aromatase activity.

Sulphamate Group

The term “sulphamate” as used herein includes an ester of sulphamicacid, or an ester of an N-substituted derivative of sulphamic acid, or asalt thereof.

If R₉ is a sulphamate group then the compound of the present inventionis referred to as a sulphamate compound.

Typically, the sulphamate group has the formula:(R₁)(R₂)N—S(O)(O)—O—wherein preferably R₁ and R₂ are independently selected from H, alkyl,cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or togetherrepresent alkylene, wherein the or each alkyl or cycloalkyl or alkenylor optionally contain one or more hetero atoms or groups.

When substituted, the N-substituted compounds of this invention maycontain one or two N-alkyl, N-alkenyl, N-cycloalkyl or N-arylsubstituents, preferably containing or each containing a maximum of 10carbon atoms.

When R₁ and/or R₂ is hydrocarbyl, the preferred values are those whereR₁ and R₂ are each independently selected C₁-C₁₀ hydrocarbyl, C₁-C₅hydrocarbyl, C₁-C₃ hydrocarbyl, C₁-C₁₀ hydrocarbon, C₁-C₅ hydrocarbon,C₁-C₃ hydrocarbon, C₁-C₁₀ alkyl, C₁-C₅ alkyl and C₁-C₃ alkyl.

When R₁ and/or R₂ is alkyl, the preferred values are those where R₁ andR₂ are each independently selected from lower alkyl groups containingfrom 1 to 6 carbon atoms, that is to say methyl, ethyl, propyl etc. R₁and R₂ may both be methyl.

When R₁ and/or R₂ is aryl, typical values are phenyl and tolyl (PhCH₃;o).

Where R₁ and/or R₂ represent cycloalkyl, typical values are cyclopropyl,cyclopentyl, cyclohexyl etc.

When joined together R₁ and R₂ typically represent an alkylene groupproviding a chain of 4 to 6 carbon atoms, optionally interrupted by oneor more hetero atoms or groups, e.g. to provide a 5 memberedheterocycle, e.g. morpholino, pyrrolidino or piperidino.

Within the values alkyl, cycloalkyl, alkenyl, acyl and aryl substitutedgroups are included containing as substituents therein one or moregroups which do not interfere with the sulphatase inhibitory activity ofthe compound in question. Exemplary non-interfering substituents includehydroxy, amino, halo, alkoxy, alkyl and aryl.

In some embodiments, the sulphamate group may form a ring structure bybeing fused to (or associated with) one or more atoms in or on ring A.

In some embodiments, there may be more than one sulphamate group. By wayof example, there may be two sulphamates (i.e. bis-sulphamatecompounds).

In some preferred embodiments, at least one of R₁ and R₂ is H.

In some further preferred embodiments, each of R₁ and R₂ is H.

Other Substituents

The compound of the present invention may have substituents other thanthose of formula I. By way of example, these other substituents may beone or more of: one or more sulphamate group(s), one or more phosphonategroup(s), one or more thiophosphonate group(s), one or more sulphonategroup(s), one or more sulphonamide group(s), one or more halo groups,one or more O groups, one or more hydroxy groups, one or more aminogroups, one or more sulphur containing group(s), one or more hydrocarbylgroup(s)—such as an oxyhydrocarbyl group.

Assay for Determining STS Activity Using Cancer Cells (Protocol 1)

Inhibition of Steroid Sulphatase Activity in JEG3 cells

Steroid sulphatase activity is measured in vitro using intact JEG3choriocarcinoma cells. This cell line may be used to study the controlof human breast cancer cell growth. It possesses significant steroidsulphatase activity (Boivin et al., J. Med. Chem., 2000, 43: 4465-4478)and is available in from the American Type Culture Collection (ATCC).

Cells are maintained in Minimal Essential Medium (MEM) (FlowLaboratories, Irvine, Scotland) containing 20 mM HEPES, 5% foetal bovineserum, 2 mM glutamine, non-essential amino acids and 0.075% sodiumbicarbonate. Up to 30 replicate 25 cm² tissue culture flasks are seededwith approximately 1×10⁵ cells/flask using the above medium. Cells aregrown to 80% confluency and the medium is changed every third day.

Intact monolayers of JEG3 cells in triplicate 25 cm² tissue cultureflasks are washed with Earle's Balanced Salt Solution (EBSS from ICNFlow, High Wycombe, U.K.) and incubated for 3-4 hours at 37° C. with 5pmol (7×10⁵ dpm) [6, 7-3H]oestrone-3-sulphate (specific activity 60Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in serum-freeMEM (2.5 ml) together with oestrone-3-sulphamate (11 concentrations: 0;1fM; 0.01 pM; 0.1 pM; 1 pM; 0.01 nM; 0.1 nM; 1 nM; 0.01 mM; 0.1 mM; 1mM). After incubation each flask is cooled and the medium (1 ml) ispipetted into separate tubes containing [14C]oestrone (7×103 dpm)(specific activity 97 Ci/mmol from Amersham International RadiochemicalCentre, Amersham, U.K.). The mixture is shaken thoroughly for 30 secondswith toluene (5 ml). Experiments have shown that >90% [14C]oestrone and<0.1% [3H]oestrone-3-sulphate is removed from the aqueous phase by thistreatment. A portion (2 ml) of the organic phase is removed, evaporatedand the 3H and 14C content of the residue determined by scintillationspectrometry. The mass of oestrone-3-sulphate hydrolysed was calculatedfrom the 3H counts obtained (corrected for the volumes of the medium andorganic phase used, and for recovery of [14C]oestrone added) and thespecific activity of the substrate. Each batch of experiments includesincubations of microsomes prepared from a sulphatase-positive humanplacenta (positive control) and flasks without cells (to assess apparentnon-enzymatic hydrolysis of the substrate). The number of cell nucleiper flask is determined using a Coulter Counter after treating the cellmonolayers with Zaponin. One flask in each batch is used to assess cellmembrane status and viability using the Trypan Blue exclusion method(Phillips, H. J. (1973) In: Tissue culture and applications, [eds:Kruse, D. F. & Patterson, M. K.]; pp. 406-408; Academic Press, NewYork).

Results for steroid sulphatase activity are expressed as the mean±1 S.D.of the total product (oestrone+oestradiol) formed during the incubationperiod (3-4 hours) calculated for 106 cells and, for values showingstatistical significance, as a percentage reduction (inhibition) overincubations containing no oestrone-3-sulphamate. Unpaired Student'st-test was used to test the statistical significance of results.

Assay for Determining Sts Activity Using Placental Microsomes (Protocol2)

Inhibition of Steroid Sulphatase Activity in Placental Microsomes

Sulphatase-positive human placenta from normal term pregnancies arethoroughly minced with scissors and washed once with cold phosphatebuffer (pH 7.4, 50 mM) then re-suspended in cold phosphate buffer (5ml/g tissue). Homogenisation is accomplished with an Ultra-Turraxhomogeniser, using three 10 second bursts separated by 2 minute coolingperiods in ice. Nuclei and cell debris are removed by centrifuging (4°C.) at 2000 g for 30 minutes and portions (2 ml) of the supernatant arestored at 20° C. The protein concentration of the supernatants isdetermined by the method of Bradford (Anal. Biochem., 72, 248-254(1976)).

Incubations (1 ml) are carried out using a protein concentration of 100mg/ml, substrate concentration of 20 mM [6, 7-3H]oestrone-3-sulphate(specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass.,U.S.A.) and an incubation time of 20 minutes at 37° C. If necessaryeight concentrations of compounds are employed: 0 (i.e. control); 0.05mM; 0.1 mM; 0.2 mM; 0.4 mM; 0.6 mM; 0.8 mM; 1.0 mM. After incubationeach sample is cooled and the medium (1 ml) was pipetted into separatetubes containing [14C]oestrone (7×103 dpm) (specific activity 97 Ci/mmolfrom Amersham International Radiochemical Centre, Amersham, U.K.). Themixture is shaken thoroughly for 30 seconds with toluene (5 ml).Experiments have shown that >90% [14C]oestrone and <0.1%[3H]oestrone-3-sulphate is removed from the aqueous phase by thistreatment. A portion (2 ml) of the organic phase was removed, evaporatedand the 3H and 14C content of the residue determined by scintillationspectrometry. The mass of oestrone-3-sulphate hydrolysed is calculatedfrom the 3H counts obtained (corrected for the volumes of the medium andorganic phase used, and for recovery of [14C]oestrone added) and thespecific activity of the substrate.

Animal Assay Model for Determining STS Activity (Protocol 3)

Inhibition of Oestrone Sulphatase Activity In Vivo

The compounds of the present invention may be studied using an animalmodel, in particular in ovariectomised rats. In this model compoundswhich are oestrogenic stimulate uterine growth.

The compound (0.1 mg/Kg/day for five days) is administered orally torats with another group of animals receiving vehicle only (propyleneglycol). At the end of the study samples of liver tissue were obtainedand oestrone sulphatase activity assayed using 3H oestrone sulphate asthe substrate as previously described (see PCT/GB95/02638).

Animal Assay Model for Determining Oestrogenic Activity (Protocol 4)

The compounds of the present invention may be studied using an animalmodel, in particular in ovariectomised rats. In this model, compoundswhich are oestrogenic stimulate uterine growth.

The compound (0.1 mg/Kg/day for five days) was administered orally torats with another group of animals receiving vehicle only (propyleneglycol). At the end of the study uteri were obtained and weighed withthe results being expressed as uterine weight/whole body weight ×100.

Compounds having no significant effect on uterine growth are notoestrogenic.

Biotechnological Assays for Determining STS Activity (Protocol 5)

The ability of compounds to inhibit oestrone sulphatase activity canalso be assessed using amino acid sequences or nucleotide sequencesencoding STS, or active fragments, derivatives, homologues or variantsthereof in, for example, high-through put screens.

Such assays and methods for their practice are taught in WO 03/045925which is incorporated herein by reference.

In one preferred aspect, the present invention relates to a method ofidentifying agents that selectively modulate STS, which compounds havethe formula (I).

Assay for Determining Aromatase Activity Using Jeg3 Cells (Protocol 6)

Aromatase activity is measured in JEG3 choriocarcinoma cells, obtainedfrom the ATCC. This cell line possesses significant aromatase activityand is widely used to study the control of human aromatase activity(Bhatnager et al., J. Steroid Biochem. Molec. Biol. 2001, 76: 199-202).Cells are maintained in Minimal Essential Medium (MEM, FlowLaboratories, Irvine, Scotland) containing 20 mM HEPES, 10% foetalbovine serum, 2 mM glutamine, non-essential amino acids and 0.075%sodium bicarbonate. Intact monolayers of JEG3 cells (2.5×10⁶ cells) intriplicate 25 cm² tissue culture flasks are washed with Earle's Balancedsalt solution (EBSS, from ICN Flow, High Wycombe, UK) and incubated with[1β-³H]androstenedione (2-5 nM, 26 Ci/mmol, New England Nuclear, Boston,Mass., USA) for 30 min with inhibitors over the range of 10 pm-10 μM.

During the aromatase reaction, ³H₂O is liberated which can be quantifiedusing a liquid scintillation spectrometer (Beckman-Coulter, HighWycombe, Bucks. UK). This ³H₂O-release method has been widely used tomeasure aromatase activity (Newton et al., J. Steroid Biochem. 1986, 24:1033-1039). The number of cell nuclei per flask is determined using aCoulter Counter after treating the cell monolayers with Z aponin.

Results for aromatase activity are expressed as the mean±1 S.D. of theproduct formed during the incubation period (30 min) calculated for 10⁶cells and, for values showing a statistical significance, as apercentage reduction (inhibition) over incubations containing noaromatase inhibitor. Unpaired Student's t test was used to test thestatistical significance of results. IC₅₀ values were calculated as theconcentration of inhibitor required to obtain a 50% inhibition ofaromatase activity.

Animal Assays for Determining Aromatase Activity (Protocol 7)

(i) Inhibition of PMSG-Induced Oestrogen Synthesis

The ability of compounds to inhibit aromatase activity in vivo wastested using a pregnant mare serum gonadotrophin (PMSG)-inducedoestrogen synthesis assay. For this, female rats (250 g) were injectedwith PMSG (200 IU, s.c.). After 72 h rats were administered vehicle(propylene glycol) or various doses of test compounds orally. At 2 hafter dosing blood samples were obtained by cardiac puncture (underanaesthesia). Plasma oestradiol levels were measured in control groupsand groups receiving drugs. The efficacy of aromatase inhibition wasdetermined by measurement of plasma oestradiol concentrations byradioimmunoassay. This method has been widely used to determine theeffectiveness of aromatase inhibitors in vivo (W outers et al., J.Steroid Biochem., 1989, 32: 781-788).

(ii) Inhibition of Androstenedione Stimulated Uterine Growth inOvariectomised Rats

Female rats (250 g) were ovariectomised and used to determine theeffectiveness of aromatase inhibition on androstenedione stimulateduterine growth. Administration of androstenedione (30 mg/kg/d) for a2-week period results in a significant increase in uterine growth inovariectomised animals. This increase in uterine growth is stimulated byoestrogen which is derived from the administered androstenedione as aresult of the action of the aromatase enzyme. By co-administration ofcompounds with androstenedione the extent of aromatase inhibition can bedetermined by measurements of uterine weights in treated and untreatedanimals.

Therapy

The compounds of the present invention may be used as therapeuticagents—i.e. in therapy applications.

The term “therapy” includes curative effects, alleviation effects, andprophylactic effects.

The therapy may be on humans or animals, preferably female animals.

Pharmaceutical Compositions

In one aspect, the present invention provides a pharmaceuticalcomposition, which comprises a compound according to the presentinvention and optionally a pharmaceutically acceptable carrier, diluentor excipient (including combinations thereof).

The pharmaceutical compositions may be for human or animal usage inhuman and veterinary medicine and will typically comprise any one ormore of a pharmaceutically acceptable diluent, carrier, or excipient.Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as—or in addition to—the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

There may be different composition/formulation requirements dependent onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestable solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

Combination Pharmaceutical

The compound of the present invention may be used in combination withone or more other active agents, such as one or more otherpharmaceutically active agents.

By way of example, the compounds of the present invention may be used incombination with other STS inhibitors and/or other inhibitors such as anaromatase inhibitor (such as for example, 4-hydroxyandrostenedione(4-OHA)) and/or steroids—such as the naturally occurring neurosteroidsdehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS)and/or other structurally similar organic compounds Examples of otherSTS inhibitors may be found in the above references. By way of example,STS inhibitors for use in the present invention include EMATE, andeither or both of the 2-ethyl and 2-methoxy 17-deoxy compounds that areanalogous to compound 5 presented herein.

In addition, or in the alternative, the compound of the presentinvention may be used in combination with a biological responsemodifier.

The term biological response modifier (“BRM”) includes cytokines, immunemodulators, growth factors, haematopoiesis regulating factors, colonystimulating factors, chemotactic, hemolytic and thrombolytic factors,cell surface receptors, ligands, leukocyte adhesion molecules,monoclonal antibodies, preventative and therapeutic vaccines, hormones,extracellular matrix components, fibronectin, etc. For someapplications, preferably, the biological response modifier is acytokine. Examples of cytokines include: interleukins (IL)—such as IL-1,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12,IL-19; Tumour Necrosis Factor (TNF)— such as TNF-α; Interferon alpha,beta and gamma; TGF-β. For some applications, preferably the cytokine istumour necrosis factor (TNF). For some applications, the TNF may be anytype of TNF—such as TNF-α, TNF-β, including derivatives or mixturesthereof. More preferably the cytokine is TNF-α. Teachings on TNF may befound in the art—such as WO-A-98/08870 and WO-A-98/13348.

Administration

Typically, a physician will determine the actual dosage which will bemost suitable for an individual subject and it will vary with the age,weight and response of the particular patient. The dosages below areexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited.

The compositions of the present invention may be administered by directinjection. The composition may be formulated for parenteral, mucosal,intramuscular, intravenous, subcutaneous, intraocular or transdermaladministration. Depending upon the need, the agent may be administeredat a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10mg/kg, more preferably from 0.1 to 1 mg/kg body weight.

By way of further example, the agents of the present invention may beadministered in accordance with a regimen of 1 to 4 times per day,preferably once or twice per day. The specific dose level and frequencyof dosage for any particular patient may be varied and will depend upona variety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

Aside from the typical modes of delivery—indicated above—the term“administered” also includes delivery by techniques such as lipidmediated transfection, liposomes, immunoliposomes, lipofectin, cationicfacial amphiphiles (CFAs) and combinations thereof. The routes for suchdelivery mechanisms include but are not limited to mucosal, nasal, oral,parenteral, gastrointestinal, topical, or sublingual routes.

The term “administered” includes but is not limited to delivery by amucosal route, for example, as a nasal spray or aerosol for inhalationor as an ingestable solution; a parenteral route where delivery is by aninjectable form, such as, for example, an intravenous, intramuscular orsubcutaneous route.

Thus, for pharmaceutical administration, the STS inhibitors of thepresent invention can be formulated in any suitable manner utilisingconventional pharmaceutical formulating techniques and pharmaceuticalcarriers, adjuvants, excipients, diluents etc. and usually forparenteral administration. Approximate effective dose rates may be inthe range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or evenfrom 100 to 800 mg/day depending on the individual activities of thecompounds in question and for a patient of average (70 Kg) bodyweight.More usual dosage rates for the preferred and more active compounds willbe in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day,most preferably from 200 to 250 mg/day. They may be given in single doseregimes, split dose regimes and/or in multiple dose regimes lasting overseveral days. For oral administration they may be formulated in tablets,capsules, solution or suspension containing from 100 to 500 mg ofcompound per unit dose. Alternatively and preferably the compounds willbe formulated for parenteral administration in a suitable parenterallyadministrable carrier and providing single daily dosage rates in therange 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250mg. Such effective daily doses will, however, vary depending on inherentactivity of the active ingredient and on the bodyweight of the patient,such variations being within the skill and judgement of the physician.

Cell Cycling

The compounds of the present invention may be useful in the method oftreatment of a cell cycling disorder.

As discussed in “Molecular Cell Biology” 3rd Ed. Lodish et al. pages177-181 different eukaryotic cells can grow and divide at quitedifferent rates. Yeast cells, for example, can divide every 120 min.,and the first divisions of fertilised eggs in the embryonic cells of seaurchins and insects take only 1530 min. because one large pre-existingcell is subdivided. However, most growing plant and animal cells take10-20 hours to double in number, and some duplicate at a much slowerrate. Many cells in adults, such as nerve cells and striated musclecells, do not divide at all; others, like the fibroblasts that assist inhealing wounds, grow on demand but are otherwise quiescent.

Still, every eukaryotic cell that divides must be ready to donate equalgenetic material to two daughter cells. DNA synthesis in eukaryotes doesnot occur throughout the cell division cycle but is restricted to a partof it before cell division.

The relationship between eukaryotic DNA synthesis and cell division hasbeen thoroughly analysed in cultures of mammalian cells that were allcapable of growth and division. In contrast to bacteria, it was found,eukaryotic cells spend only a part of their time in DNA synthesis, andit is completed hours before cell division (mitosis). Thus a gap of timeoccurs after DNA synthesis and before cell division; another gap wasfound to occur after division and before the next round of DNAsynthesis. This analysis led to the conclusion that the eukaryotic cellcycle consists of an M (mitotic) phase, a G₁ phase (the first gap), theS (DNA synthesis) phase, a G₂ phase (the second gap), and back to M. Thephases between mitoses (G₁, S, and G₂) are known collectively as theinterphase.

Many nondividing cells in tissues (for example, all quiescentfibroblasts) suspend the cycle after mitosis and just prior to DNAsynthesis; such “resting” cells are said to have exited from the cellcycle and to be in the G₀ state.

It is possible to identify cells when they are in one of the threeinterphase stages of the cell cycle, by using a fluorescence-activatedcell sorter (FACS) to measure their relative DNA content: a cell that isin G₁ (before DNA synthesis) has a defined amount x of DNA; during S(DNA replication), it has between x and 2x; and when in G₂ (or M), ithas 2x of DNA.

The stages of mitosis and cytokinesis in an animal cell are as follows

(a) Interphase. The G₂ stage of interphase immediately precedes thebeginning of mitosis. Chromosomal DNA has been replicated and bound toprotein during the S phase, but chromosomes are not yet seen as distinctstructures. The nucleolus is the only nuclear substructure that isvisible under light microscope. In a diploid cell before DNA replicationthere are two morphologic chromosomes of each type, and the cell is saidto be 2n. In G₂, after DNA replication, the cell is 4n. There are fourcopies of each chromosomal DNA. Since the sister chromosomes have notyet separated from each other, they are called sister chromatids.

b) Early prophase. Centrioles, each with a newly formed daughtercentriole, begin moving toward opposite poles of the cell; thechromosomes can be seen as long threads. The nuclear membrane begins todesegregate into small vesicles.

(c) Middle and late prophase. Chromosome condensation is completed; eachvisible chromosome structure is composed of two chromatids held togetherat their centromeres. Each chromatid contains one of the two newlyreplicated daughter DNA molecules. The microtubular spindle begins toradiate from the regions just adjacent to the centrioles, which aremoving closer to their poles. Some spindle fibres reach from pole topole; most go to chromatids and attach at kinetochores.

(d) Metaphase. The chromosomes move toward the equator of the cell,where they become aligned in the equatorial plane. The sister chromatidshave not yet separated.

(e) Anaphase. The two sister chromatids separate into independentchromosomes. Each contains a centromere that is linked by a spindlefibre to one pole, to which it moves. Thus one copy of each chromosomeis donated to each daughter cell. Simultaneously, the cell elongates, asdo the pole-to-pole spindles. Cytokinesis begins as the cleavage furrowstarts to form.

(f) Telophase. New membranes form around the daughter nuclei; thechromosomes uncoil and become less distinct, the nucleolus becomesvisible again, and the nuclear membrane forms around each daughternucleus. Cytokinesis is nearly complete, and the spindle disappears asthe microtubules and other fibres depolymerise. Throughout mitosis the“daughter” centriole at each pole grows until it is full-length. Attelophase the duplication of each of the original centrioles iscompleted, and new daughter centrioles will be generated during the nextinterphase.

(g) Interphase. Upon the completion of cytokinesis, the cell enters theG₁ phase of the cell cycle and proceeds again around the cycle.

It will be appreciated that cell cycling is an extremely important cellprocess. Deviations from normal cell cycling can result in a number ofmedical disorders. Increased and/or unrestricted cell cycling may resultin cancer. Reduced cell cycling may result in degenerative conditions.Use of the compound of the present invention may provide a means totreat such disorders and conditions.

Thus, the compound of the present invention may be suitable for use inthe treatment of cell cycling disorders such as cancers, includinghormone dependent and hormone independent cancers.

In addition, the compound of the present invention may be suitable forthe treatment of cancers such as breast cancer, ovarian cancer,endometrial cancer, sarcomas, melanomas, prostate cancer, pancreaticcancer etc. and other solid tumours.

For some applications, cell cycling is inhibited and/or prevented and/orarrested, preferably wherein cell cycling is prevented and/or arrested.In one aspect cell cycling may be inhibited and/or prevented and/orarrested in the G₂/M phase. In one aspect cell cycling may beirreversibly prevented and/or inhibited and/or arrested, preferablywherein cell cycling is irreversibly prevented and/or arrested.

By the term “irreversibly prevented and/or inhibited and/or arrested” itis meant after application of a compound of the present invention, onremoval of the compound the effects of the compound, namely preventionand/or inhibition and/or arrest of cell cycling, are still observable.More particularly by the term “irreversibly prevented and/or inhibitedand/or arrested” it is meant that when assayed in accordance with thecell cycling assay protocol presented herein, cells treated with acompound of interest show less growth after Stage 2 of the protocol Ithan control cells. Details on this protocol are presented below.

Thus, the present invention provides compounds which: cause inhibitionof growth of oestrogen receptor positive (ER+) and ER negative (ER−)breast cancer cells in vitro by preventing and/or inhibiting and/orarresting cell cycling; and/or cause regression of nitroso-methyl urea(NMU)-induced mammary tumours in intact animals (i.e. notovariectomised), and/or prevent and/or inhibit and/or arrest cellcycling in cancer cells; and/or act in vivo by preventing and/orinhibiting and/or arresting cell cycling and/or act as a cell cyclingagonist.

Cell Cycling Assay (Protocol 7)

Procedure

Stage 1

MCF-7 breast cancer cells are seeded into multi-well culture plates at adensity of 105 cells/well. Cells were allowed to attach and grown untilabout 30% confluent when they are treated as follows:

Control—no treatment

Compound of Interest (COI) 20 μM

Cells are grown for 6 days in growth medium containing the COI withchanges of medium/COI every 3 days. At the end of this period cellnumbers were counted using a Coulter cell counter.

Stage 2

After treatment of cells for a 6-day period with the COI cells arere-seeded at a density of 10⁴ cells/well. No further treatments areadded. Cells are allowed to continue to grow for a further 6 days in thepresence of growth medium. At the end of this period cell numbers areagain counted.

Cancer

As indicated, the compounds of the present invention may be useful inthe treatment of a cell cycling disorder. A particular cell cyclingdisorder is cancer.

Cancer remains a major cause of mortality in most Western countries.Cancer therapies developed so far have included blocking the action orsynthesis of hormones to inhibit the growth of hormone-dependenttumours. However, more aggressive chemotherapy is currently employed forthe treatment of hormone-independent tumours.

Hence, the development of a pharmaceutical for anti-cancer treatment ofhormone dependent and/or hormone independent tumours, yet lacking someor all of the side-effects associated with chemotherapy, would representa major therapeutic advance.

It is known that oestrogens undergo a number of hydroxylation andconjugation reactions after their synthesis. Until recently it wasthought that such reactions were part of a metabolic process thatultimately rendered oestrogens water soluble and enhanced theirelimination from the body. It is now evident that some hydroxymetabolites (e.g. 2-hydroxy and 16alpha-hydroxy) and conjugates (e.g.oestrone sulphate, E1S) are important in determining some of the complexactions that oestrogens have in the body.

Workers have investigated the formation of 2- and 16-hydroxylatedoestrogens in relation to conditions that alter the risk of breastcancer. There is now evidence that factors which increase 2-hydroxylaseactivity are associated with a reduced cancer risk, while thoseincreasing 16alpha-hydroxylation may enhance the risk of breast cancer.Further interest in the biological role of estrogen metabolites has beenstimulated by the growing body of evidence that 2-methoxyoestradiol isan endogenous metabolite with anti-mitotic properties. 2-MeOE2 is formedfrom 2-hydroxy estradiol (2-OHE2) by catechol estrogen methyltransferase, an enzyme that is widely distributed throughout the body.

Workers have shown that in vivo 2-MeOE2 inhibits the growth of tumoursarising from the subcutaneous injection of Meth A sarcoma, B16 melanomaor MDA-MB-435 estrogen receptor negative (ER−) breast cancer cells. Italso inhibits endothelial cell proliferation and migration, and in vitroangiogenesis. It was suggested that the ability of 2-MeOE2 to inhibittumour growth in vivo may be due to its ability to inhibittumour-induced angiogenesis rather than direct inhibition of theproliferation of tumour cells.

The mechanism by which 2-MeOE2 exerts its potent anti-mitogenic andanti-angiogenic effects is still being elucidated. There is evidencethat at high concentrations it can inhibit microtubule polymerisationand act as a weak inhibitor of colchicine binding to tubulin. Recently,however, at concentrations that block mitosis, tubulin filaments incells were not found to be depolymerised but to have an identicalmorphology to that seen after taxol treatment. It is possible,therefore, that like taxol, a drug that is used for breast and ovarianbreast cancer therapy, 2-MeOE2 acts by stabilising microtubule dynamics.

While the identification of 2-MeOE2 as a new therapy for cancerrepresents an important advance, the bioavailability of orallyadministered oestrogens is poor. Furthermore, they can undergo extensivemetabolism during their first pass through the liver. As part of aresearch programme to develop a steroid sulphatase inhibitor for breastcancer therapy, oestrone-3-O-sulphamate (EMATE) was identified as apotent active site-directed inhibitor. Unexpectedly, EMATE proved topossess potent oestrogenic properties with its oral uterotrophicactivity in rats being a 100-times higher than that of estradiol. Itsenhanced oestrogenicity is thought to result from its absorption by redblood cells (rbcs) which protects it from inactivation during itspassage through the liver and which act as a reservoir for its slowrelease for a prolonged period of time. A number of A-ring modifiedanalogues were synthesised and tested, including2-methoxyoestrone-3-O-sulphamate. While this compound was equipotentwith EMATE as a steroid sulphatase inhibitor, it was devoid ofoestrogenicity.

Applicants believe that the compound of the present invention provides ameans for the treatment of cancers and, especially, breast cancer.

In addition or in the alternative the compound of the present inventionmay be useful in the blocking the growth of cancers including leukaemiasand solid tumours such as breast, endometrium, prostate, ovary andpancreatic tumours.

Therapy Concerning Oestrogen

Applicants believe that some of the compounds of the present inventionmay be useful in the control of oestrogen levels in the body—inparticular in females. Thus, some of the compounds may be useful asproviding a means of fertility control—such as an oral contraceptivetablet, pill, solution or lozenge. Alternatively, the compound could bein the form of an implant or as a patch.

Thus, the compounds of the present invention may be useful in treatinghormonal conditions associated with oestrogen.

In addition or in the alternative the compound of the present inventionmay be useful in treating hormonal conditions in addition to thoseassociated with oestrogen. Hence, the compound of the present inventionmay also be capable of affecting hormonal activity and may also becapable of affecting an immune response.

Neurodegenerative Diseases

Applicants believe that some of the compounds of the present inventionmay be useful in the treatment of neurogenerative diseases, and similarconditions.

By way of example, it is believed that STS inhibitors may be useful inthe enhancing the memory function of patients suffering from illnessessuch as amnesia, head injuries, Alzheimer's disease, epileptic dementia,presenile dementia, post traumatic dementia, senile dementia, vasculardementia and post-stroke dementia or individuals otherwise seekingmemory enhancement.

TH1

Applicants believe that some of the compounds of the present inventionmay be useful in regulating TH1 cytokine response.

By way of example, it is believed that the presence of STS inhibitorswithin the macrophage or other antigen presenting cells may lead to adecreased ability of sensitised T cells to mount a TH1 (high IL-2, IFNγlow IL-4) response. The normal regulatory influence of other steroidssuch as glucocorticoids would therefore predominate.

Inflamatory Conditions

Applicants believe that some of the compounds of the present inventionmay be useful in treating inflammatory conditions—such as conditionsassociated with any one or more of: autoimmunity, including for example,rheumatoid arthritis, type I and II diabetes, systemic lupuserythematosus, multiple sclerosis, myasthenia gravis, thyroiditis,vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g.psoriasis and contact dermatitis; graft versus host disease; eczema;asthma and organ rejection following transplantation.

By way of example, it is believed that STS inhibitors may prevent thenormal physiological effect of DHEA or related steroids on immune and/orinflammatory responses.

The compounds of the present invention may be useful in the manufactureof a medicament for revealing an endogenous glucocorticoid-like effect.

Other Therapies

It is also to be understood that the compound/composition of the presentinvention may have other important medical implications.

For example, the compound or composition of the present invention may beuseful in the treatment of the disorders listed in WO-A-99/52890—viz:

In addition, or in the alternative, the compound or composition of thepresent invention may be useful in the treatment of the disorders listedin WO-A-98/05635. For ease of reference, part of that list is nowprovided: cancer, inflammation or inflammatory disease, dermatologicaldisorders, fever, cardiovascular effects, hemorrhage, coagulation andacute phase response, cachexia, anorexia, acute infection, HIVinfection, shock states, graft-versus-host reactions, autoimmunedisease, reperfusion injury, meningitis, migraine and aspirin-dependentanti-thrombosis; tumour growth, invasion and spread, angiogenesis,metastases, malignant, ascites and malignant pleural effusion; cerebralischaemia, ischaemic heart disease, osteoarthritis, rheumatoidarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration,Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn'sdisease and ulcerative colitis; periodontitis, gingivitis; psoriasis,atopic dermatitis, chronic ulcers, epidermolysis bullosa; cornealulceration, retinopathy and surgical wound healing; rhinitis, allergicconjunctivitis, eczema, anaphylaxis; restenosis, congestive heartfailure, endometriosis, atherosclerosis or endosclerosis.

In addition, or in the alternative, the compound or composition of thepresent invention may be useful in the treatment of disorders listed inWO-A-98/07859. For ease of reference, part of that list is now provided:cytokine and cell proliferation/differentiation activity;immunosuppressant or immunostimulant activity (e.g. for treating immunedeficiency, including infection with human immune deficiency virus;regulation of lymphocyte growth; treating cancer and many autoimmunediseases, and to prevent transplant rejection or induce tumourimmunity); regulation of haematopoiesis, e.g. treatment of myeloid orlymphoid diseases; promoting growth of bone, cartilage, tendon, ligamentand nerve tissue, e.g. for healing wounds, treatment of burns, ulcersand periodontal disease and neurodegeneration; inhibition or activationof follicle-stimulating hormone (modulation of fertility);chemotactic/chemokinetic activity (e.g. for mobilising specific celltypes to sites of injury or infection); haemostatic and thrombolyticactivity (e.g. for treating haemophilia and stroke); antiinflammatoryactivity (for treating e.g. septic shock or Crohn's disease); asantimicrobials; modulators of e.g. metabolism or behaviour; asanalgesics; treating specific deficiency disorders; in treatment of e.g.psoriasis, in human or veterinary medicine.

In addition, or in the alternative, the composition of the presentinvention may be useful in the treatment of disorders listed inWO-A-98/09985. For ease of reference, part of that list is now provided:macrophage inhibitory and/or T cell inhibitory activity and thus,anti-inflammatory activity; anti-immune activity, i.e. inhibitoryeffects against a cellular and/or humoral immune response, including aresponse not associated with inflammation; inhibit the ability ofmacrophages and T cells to adhere to extracellular matrix components andfibronectin, as well as up-regulated fas receptor expression in T cells;inhibit unwanted immune reaction and inflammation including arthritis,including rheumatoid arthritis, inflammation associated withhypersensitivity, allergic reactions, asthma, systemic lupuserythematosus, collagen diseases and other autoimmune diseases,inflammation associated with atherosclerosis, arteriosclerosis,atherosclerotic heart disease, reperfusion injury, cardiac arrest,myocardial infarction, vascular inflammatory disorders, respiratorydistress syndrome or other cardiopulmonary diseases, inflammationassociated with peptic ulcer, ulcerative colitis and other diseases ofthe gastrointestinal tract, hepatic fibrosis, liver cirrhosis or otherhepatic diseases, thyroiditis or other glandular diseases,glomerulonephritis or other renal and urologic diseases, otitis or otheroto-rhino-laryngological diseases, dermatitis or other dermal diseases,periodontal diseases or other dental diseases, orchitis orepididimo-orchitis, infertility, orchidal trauma or other immune-relatedtesticular diseases, placental dysfunction, placental insufficiency,habitual abortion, eclampsia, pre-eclampsia and other immune and/orinflammatory-related gynaecological diseases, posterior uveitis,intermediate uveitis, anterior uveitis, conjunctivitis, chorioretinitis,uveoretinitis, optic neuritis, intraocular inflammation, e.g. retinitisor cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitispigmentosa, immune and inflammatory components of degenerative fondusdisease, inflammatory components of ocular trauma, ocular inflammationcaused by infection, proliferative vitreo-retinopathies, acute ischaemicoptic neuropathy, excessive scarring, e.g. following glaucoma filtrationoperation, immune and/or inflammation reaction against ocular implantsand other immune and inflammatory-related ophthalmic diseases,inflammation associated with autoimmune diseases or conditions ordisorders where, both in the central nervous system (CNS) or in anyother organ, immune and/or inflammation suppression would be beneficial,Parkinson's disease, complication and/or side effects from treatment ofParkinson's disease, AIDS-related dementia complex HIV-relatedencephalopathy, Device's disease, Sydenham chorea, Alzheimer's diseaseand other degenerative diseases, conditions or disorders of the CNS,inflammatory components of stokes, post-polio syndrome, immune andinflammatory components of psychiatric disorders, myelitis,encephalitis, subacute sclerosing pan-encephalitis, encephalomyelitis,acute neuropathy, subacute neuropathy, chronic neuropathy,Guillaim-Barre syndrome, Sydenham chora, myasthenia gravis,pseudo-tumour cerebri, Down's Syndrome, Huntington's disease,amyotrophic lateral sclerosis, inflammatory components of CNScompression or CNS trauma or infections of the CNS, inflammatorycomponents of muscular atrophies and dystrophies, and immune andinflammatory related diseases, conditions or disorders of the centraland peripheral nervous systems, post-traumatic inflammation, septicshock, infectious diseases, inflammatory complications or side effectsof surgery, bone marrow transplantation or other transplantationcomplications and/or side effects, inflammatory and/or immunecomplications and side effects of gene therapy, e.g. due to infectionwith a viral carrier, or inflammation associated with AIDS, to suppressor inhibit a humoral and/or cellular immune response, to treat orameliorate monocyte or leukocyte proliferative diseases, e.g. leukaemia,by reducing the amount of monocytes or lymphocytes, for the preventionand/or treatment of graft rejection in cases of transplantation ofnatural or artificial cells, tissue and organs such as cornea, bonemarrow, organs, lenses, pacemakers, natural or artificial skin tissue.

Compound Preparation

The compounds of the present invention may be prepared by reacting anappropriate alcohol with a suitable chloride. By way of example, thesulphamate compounds of the present invention may be prepared byreacting an appropriate alcohol with a suitable sulfamoyl chloride, ofthe formula R₃R₄NSO₂Cl.

Typical conditions for carrying out the reaction are as follows.

Sodium hydride and a sulfamoyl chloride are added to a stirred solutionof the alcohol in anhydrous dimethyl formamide at 0° C. Subsequently,the reaction is allowed to warm to room temperature whereupon stirringis continued for a further 24 hours. The reaction mixture is poured ontoa cold saturated solution of sodium bicarbonate and the resultingaqueous phase is extracted with dichloromethane. The combined organicextracts are dried over anhydrous MgSO₄. Filtration followed by solventevaporation in vacuo and co-evaporated with toluene affords a cruderesidue which is further purified by flash chromatography.

Preferably, the alcohol is derivatised, as appropriate, prior toreaction with the sulfamoyl chloride. Where necessary, functional groupsin the alcohol may be protected in known manner and the protecting groupor groups removed at the end of the reaction.

Preferably, the sulphamate compounds are prepared according to theteachings of Page et al (1990 Tetrahedron 46; 2059-2068).

The phosphonate compounds may be prepared by suitably combining theteachings of Page et al (1990 Tetrahedron 46; 2059-2068) andPCT/GB92/01586.

The sulphonate compounds may be prepared by suitably adapting theteachings of Page et al (1990 Tetrahedron 46; 2059-2068) andPCT/GB92/01586.

The thiophosphonate compounds may be prepared by suitably adapting theteachings of Page et al (1990 Tetrahedron 46; 2059-2068) andPCT/GB91/00270.

Preferred preparations are also presented in the following text.

SUMMARY

In summation, the present invention provides novel compounds for use assteroid sulphatase inhibitors and/or aromatase inhibitors and/ormodulators of apoptosis and/or modulators of cell cycling and/or cellgrowth, and pharmaceutical compositions containing them.

EXAMPLES

The present invention will now be described in further detail by way ofexample only with reference to the accompanying figure in which:—

FIG. 1 shows a summary scheme; and

FIG. 2 shows a summary scheme.

The present invention will now be described only by way of example.However, it is to be understood that the examples also present preferredcompounds of the present invention, as well as preferred routes formaking same and useful intermediates in the preparation of same.

Experimental

General Methods

NMR Spectra were recorded on Jeol 270 MHz or Bruker 400 MHz instruments.Low resolution mass spectra were obtained from a Micromass platform LCZ(APCI+). HPLC data was obtained from a Waters Alliance-HT-2790 machinewith a Symmetry ^(R) C18 column. Unless otherwise stated HPLC gradesolvents were used and commercial reagents and starting materials wereused without further purification. Thin layer chromatography wasundertaken using Kieselgel 60 F₂₅₄ plates (Merck). For automatedchromatography the Arganaut parallel purification system Flashmaster IIwas used with Argonaut pre-packed silica columns of specified size.Elution methods employed:

-   method1: 0.00 min, 100% hexane; 5.00 min, 50% hexane, 50% EtOAc;    10.00 min, 50% hexane, 50% EtOAc; 12.00 min, 100% EtOAc; 20.00 min,    100% EtOAc; 20.01 min, 100% hexane; 25.00 min, 100% hexane.-   method2: 0.00 min, 100% hexane; 5.00 min, 50% hexane, 50% EtOAc;    10.00 min, 50% hexane, 50% EtOAc; 12.50 min, 100% EtOAc; 25.00 min,    100% EtOAc; 25.01 min, 100% hexane; 30.00 min, 100% hexane.-   method3: 0.00 min, 100% dichloromethane; 2.50 min, 100% hexane; 7.50    min, 50% hexane, 50% EtOAc; 12.50 min, 75% EtOAc, 25%    dichloromethane; 15.00 min, 100% EtOAc; 25.00 min, 100% EtOAc; 25.01    min, 100% hexane; 30.00 min, 100% hexane.-   method4: 0.00 min, 100% dichloromethane; 2.50 min, 100% hexane; 7.50    min, 50% hexane, 50% EtOAc; 12.50 min, 75% EtOAc, 25%    dichloromethane; 20.00 min, 100% EtOAc; 30.00 min, 100% EtOAc; 30.01    min, 100% hexane; 35.00 min, 100% hexane.-   method5: 0.00 min, 100% hexane; 10.00 min, 100% EtOAc; 20.00 min,    100% EtOAc; 20.01 min, 90% EtOAc, 10% MeOH, 25.00 min, 90% EtOAc,    10% MeOH, 25.01 min, 100% hexane; 30.00 min, 100% hexane.-   method6: 0.00 min, 100% EtOAc; 20.00 min, 100% EtOAc; 20.01 min, 90%    EtOAc, 10% MeOH, 30.00 min, 90% EtOAc, 10% MeOH, 30.01 min, 100%    hexane; 35.00 min, 100% hexane.-   method7: 0.00 min, 100% dcm; 7.50 min, 100% dcm; 7.51 min, 100%    hexane; 20.00 min, 100% EtOAc; 30.00 min, 100% EtOAc; 30.01, 100%    hexane; 35.00 min, 100% hexane.-   method8: 0.00 min, 100% hexane; 5.00 min, 100% hexane; 15.00 min,    100% dcm; 25.00 min, 100% EtOAc; 35.00 min, 100% EtOAc; 35.01 min,    100% hexane; 40.00 min, 100% hexane.-   method9: 0.00 min, 100% EtOAc; 25.00 min, 100% EtOAc; 25.01 min, 90%    EtOAc, 10% MeOH, 35.00 min, 90% EtOAc, 10% MeOH, 35.01 min, 100%    hexane; 38.00 min, 100% hexane.-   method10: 0.00 min, 100% hexane; 10.00 min, 100% EtOAc; 20.00 min,    100% EtOAc; 20.01 min, 100% hexane; 25.00 min, 100% hexane.    Synthetic Routes

Compounds in accordance with the present invention were synthesised inaccordance with the synthetic routes and schemes.

6-Hydroxynaphthalen-2-yl-2-boronic acid (TJA02057)

C₁₀H₉BO₃ MW 187.99

A dry 250 ml r.b. flask was loaded with 6-bromo-2-naphthol (5.38 g, 24.1mmol) and purged with N_(2 (g)). Anhydrous THF (80 mL) added withstirring and the vessel cooled to −78° C. (dry ice/acetone bath). After30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was addeddropwise over 20 min. The reaction was left to stir for 1 h.Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with thereaction still at −78° C. After 15 min of stirring at this temperaturethe dry ice/acetone bath was removed. At 0° C. 2 M HCl_((aq)) (5 mL) wasadded and the reaction left to stir for a further 15 min. THF removedunder vacuum and residues taken up in distilled water (20 mL) anddichloromethane (50 mL) added. The resulting white precipitate wasfiltered and washed with dichloromethane and distilled water. Driedunder vacuum at 70° C. to give the title compound as an off white solid(1.88 g, 43%).

¹H NMR (270 MHz, DMSO-d₆) δ 7.04-7.08 (2H, m, ArH), 7.58-7.61 (1H, d,J=8.4 Hz, ArH), 7.73-7.76 (2H, d, J=8.4 Hz, ArH), 7.72-7.73 (1H, d,J=1.5 Hz, ArH), 8.06 (2H, s, ArB(OH)₂), 8.23 (1H, s, ArH) and 9.83 (1H,s, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=5.431 (97.67%);

LCMS (APCI), m/z 187.04 (M⁻-H, 100%), 142.92 ((M⁻-H)— B(OH)₂, 55).

1-Bromo-3-bromomethyl-5-methylbenzene (TJA01023)

C₈H₈Br₂ MW 263.96

To a solution of sodium bromate (24.4 g, 162 mmol) in distilled H₂O (40mL) was added 5-bromo-m-xylene (10.0 g, 54.0 mmol) in cyclohexane (108mL). To this clear mixture a solution of sodium hydrogen sulphate (30.8g, 162 mmol) in distilled H₂O (81 mL) was added drop wise with vigorousstirring over 60 min. The reaction mixture was stirred for a further 3 hat room temperature. The ethyl acetate was separated and diethyl ether(100 mL) added. This was then washed with saturated Na₂SO_(3 (aq)) (100mL), distilled water (100 ml×2) and brine (100 mL). Dried over Na₂SO₄and solvent removed in vacuo to leave a clear syrup. Columnchromatography (hexane) eluted the title compound as a clear oil thatcrystallised on standing to give a white crystalline solid that was usedwithout further purification (8.45 g, 60%);

R_(f) 0.52 (hexane), c.f 0.52 (dibromobenzylbromide), 0.45(1,5-dibenzylbromide), 0.6 (5-bromo-m-xylene).

¹H NMR (270 MHz, CDCl₃) δ 2.31 (3H, s, ArCH₃), 4.38 (2H, s, ArCH₂Br),7.11 (1H, s, ArH), 7.25 (1H, s, ArH) and 7.32 (1H, s, ArH);

HPLC (60% CH₃CN in H₂O) t_(r)=3.877 (67%), 4.644 (31%,dibromobenzylbromide).

(3-Bromo-5-methyl-phenyl)acetonitrile (TJA01029)

C₉H₈BrN MW 210.07

TJA01023 (11.3 g, 42.7 mmol), potassium cyanide (3.34 g, 51.2 mmol) andtetrabutylammonium bromide (0.700 g, 2.10 mmol) were loaded to an r.b.flask together with dichloromethane (60 mL) and distilled water (15 mL).With vigorous stirring the reaction mixture was set to reflux (45° C.)for 24 h. On cooling the organic fraction was separated and washed withdistilled water (50 mL×2) and brine (50 mL) then dried over Na₂SO₄ andsolvent removed in vacuo to leave a red/orange oil. Columnchromatography initially eluting with hexane separated thedibromobenzylbromide impurity. Further elution withhexane/dichloromethane (50:50) gave the title compound as a clear yellowoil (6.63 g, 74%),

R_(f) 0.54 (hexane/dichloromethane 50:50)

¹H NMR (270 MHz, CDCl₃) δ 2.31 (3H, s, ArCH₃), 3.66 (2H, s, ArCH₂CN),7.06 (1H, s, ArH), 7.25 (1H, s, ArH) and 7.27 (1H, s, ArH);

¹³C NMR (100.5 MHz, CDCl₃) δ 21.1, 23.2, 117.4, 122.8, 127.4, 128.1,131.7, 131.9 and 141.1;

HPLC (80% CH₃CN in H₂O) t_(r)=2.278 (72.5%);

LCMS (APCI), m/z 211.78 (⁸¹BrM⁺+H, 53%), 209.78 (⁷⁹BrM⁺+H, 55), 184.83((⁸¹BrM⁺+H)—CN, 80), 182.83 ((⁷⁹BrM⁺+H)—CN, 76).

2-(3-Bromo-5-methylphenyl)-2-methyl-propionitrile (TJA01035)

C₁₁H₁₂BrN MW 238.13

To a dry r.b. flask purged with N_(2 (g)) was added TJA01029 (6.00 g,28.6 mmol) and dry THF (20 mL). With stirring this was cooled via anice-water bath and NaH (1.71 g, 71.4 mmol) was added gradually and thenleft to stir at 0° C. under N_(2 (g)) for 15 min. Iodomethane (3.91 mL,62.8 mmol) was then added dropwise. The resulting suspension was left tostir at room temperature for 16 h. Propan-2-ol (5 mL) was carefullyadded to the reaction mixture followed by dichloromethane (50 mL) andwashed with distilled H₂O (50 mL×2) and brine (50 mL). Dried over Na₂SO₄and solvent removed in vacuo to leave a red/orange oil. Columnchromatography (hexane/dichloromethane 50:50) eluted the title compoundas a light yellow oil (5.65 g, 83%);

R_(f)0.38 (hexane/dichloromethane 50:50), c.f. 0.26(3-Bromo-5-methyl-phenyl)acetonitrile;

¹H NMR (270 MHz, CDCl₃) δ 1.68 (6H, s, ArC(CH₃)₂CN), 2.33 (3H, s,ArCH₃), 7.20 (1H, s, ArH), 7.26 (1H, s, ArH) and 7.34 (1H, s, ArH);

¹³C NMR (100.5 MHz, CDCl₃) δ 21.3 (CH₃), 29.0 (CH₃), 36.9 (C), 122.8,124.1, 124.9, 125.2, 131.6, 140.9 and 143.4;

HPLC (80% CH₃CN in H₂O) t_(r)=2.600 (89.65%);

LCMS (APCI), m/z 239.93 (⁸¹BrM⁺+H, 3%), 237.93 (⁷⁹BrM⁺+H, 4), 212.92((⁸¹BrM⁺+H)—CN, 100), 210.92 ((⁷⁹BrM⁺+H)—CN, 96).

2-(3-Bromo-5-bromomethyl-phenyl)-2-methylpropionitrile (TJA01036)

C₁₁H₁₁Br₂N MW 317.03

To a solution of sodium bromate (9.51 g, 63.0 mmol) in distilled H₂O (32mL) was added TJA01035 (5.00 g, 21.0 mmol) in cylcohexane (42 mL). Tothis clear mixture a solution of sodium hydrogen sulphate (7.56 g, 63.0mmol) in distilled H₂O (63 mL) was added drop wise with vigorousstirring over 1 h. The reaction mixture was stirred for a further 4 h atroom temperature. The cyclohexane was separated and diethyl ether (100mL) added. This was then washed with saturated Na₂SO_(3 (aq)) (50 mL),distilled water (50 ml×2) and brine (50 mL). Dried over Na₂SO₄ andsolvent removed in vacuo to leave viscous orange oil. Columnchromatography (hexane/dichloromethane 50:50) eluted starting materialand the title compound as a clear viscous oil (3.64 g, 54%),

R_(f) 0.55 (hexane/dichloromethane 50:50), c.f. 0.38(2-(3-bromo-5-methylphenyl)-2-methyl-propionitrile);

¹H NMR (270 MHz, CDCl₃) δ 1.71 (6H, s, ArC(CH₃)₂CN), 4.41 (2H, s,ArCH₂Br), 7.40-7.41 (1H, t, J=1.7, ArH) and 7.48-7.51 (2H, m, ArH);

HPLC (80% CH₃CN in H₂O) t_(r)=2.508 (83.05%);

LRMS (FAB), m/z 319.1 (⁸¹BrM⁺+H, 100%), 317.1 (⁷⁹BrM⁺+H, 100).

2-(3-Bromo-5-[1,2,4-triazole-1-yl-methylphenyl)-2-methylpropionitrile(TJA01037, STX1453)

C₁₃H₁₃BrN₄ MW 305.18

TJA01036 (3.20 g, 10.1 mmol), 1,2,4-triazole (1.05 g, 15.2 mmol),potassium carbonate (1.40 g, 10.1 mmol), potassium iodide (0.10 g, 0.600mmol) and acetone (150 mL) were loaded to an r.b. flask. With vigorousstirring this mixture was set to reflux (60° C.) for 24 h. The reactionmixture was allowed to cool and acetone was removed in vacuo. Theresidues were taken up in ethyl acetate (50 mL) and washed withdistilled water (50 mL×2), 1M NaOH (50 mL×1) and brine (50 mL). Driedover Na₂SO₄ and solvent removed in vacuo to leave a yellow oil. Columnchromatography (ethyl acetate) eluted the title compound as a clearviscous oil that crystallised on standing to give a colourlesscrystalline solid (1.97 g, 64%),

mp 70.9-71.8° C.;

R_(f) 0.24 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 1.68 (6H, s, ArC(CH₃)₂CN), 5.33 (2H, s,ArCH₂N), 7.40-7.41 (2H, t, J=1.7, ArH), 7.54-7.55 (1H, t, J=1.7, ArH),7.99 (1H, s, C₂H₂N₃) and 8.12 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 29.0 (CH₃), 37.0 (C), 52.6 (CH₂), 123.5,123.7, 128.6, 130.4, 137.7, 143.4, 144.5 and 152.6 (one overlappingpeak);

HPLC (60% CH₃CN in H₂O increasing to 95% over 10 min) t_(r)=2.293(98.87%); MS (EI), m/z 307.09 (⁸¹BrM⁺+H, 100%), 305.09 (⁷⁹BrM⁺+H, 99),238.01 ((⁸¹BrM⁺+H)—C₂H₂N₃, 22), 236.01 ((⁷⁹BrM⁺+H)—C₂H₂N₃, 24).

2-(3-((1H-1,2,4-Triazol-1-yl)methyl)-5-(2-hydroxynaphthalen-6-yl)phenyl)-2-methylpropanenitrile(TJA02061)

C₂₃H₂₀H₄O MW 368.43

A 10 mL microwave vial was loaded with TJA02004 (0.150 g, 0.492 mmol),TJA02057 (0.138 g, 0.737 mmol), potassium carbonate (0.170 g, 1.23mmol), tetrabutylammonium bromide (0.164 g, 0.492 mmol), Pd(OAc)₂(0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 10 min at 150° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) which eluted the titlecompound as a light yellow solid (0.130 g, 72%),

mp 193.7-198.4° C.;

R_(f): 0.42 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 1.76 (6H, s, ArC(CH₃)₂CN), 5.55 (2H, s,ArCH₂N), 7.11-7.21 (2H, m, ArH), 7.47 (1H, s, ArH), 7.66 (1H, s, ArH),7.68-7.72 (1H, dd, J=1.8 & 8.7 Hz, ArH), 7.79-7.81 (2H, m, ArH),7.85-7.88 (1H, d, J=8.7 Hz, ArH), 8.02 (1H, s, C₂H₂N₃), 8.09 (1H, s,ArH), 8.76 (1H, s, C₂H₂N₃) and 9.88 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 28.9 (CH₃), 37.4 (C), 52.6 (CH₂), 109.0(CH), 119.8 (CH), 123.6 (CH), 124.1 (CH), 125.1 (C), 125.8 (CH), 126.1(CH), 126.4 (CH), 127.4 (CH), 128.4 (C), 130.5 (CH), 134.0 (C), 134.7(C), 138.2 (C), 142.0 (C), 143.3 (C), 145.0 (CH), 152.4 (CH) and 156.3(C);

HPLC (90% CH₃CN in H₂O) t_(r)=3.697 (100%);

LCMS (APCI), m/z 369.65 (M⁺+H, 100%).

1-(3-Bromobenzyl)-1H-(1,2,4)-triazole (TJA01009, STX1360)

C₉H₈BrN₃ MW 238.08

To a solution of 3-bromobenzylbromide (20.0 g, 80.0 mmol) in acetone(300 mL) was added 1,2,4-triazole (10.8 g, 120 mmol), potassiumcarbonate (11.0 g, 80.0 mmol) and potassium iodide (0.790 g, 4.72 mmol).The resulting white suspension was heated to 55° C. with vigorousstirring for 16 h. The yellow reaction mixture was cooled and ethylacetate (100 mL) added. This was then washed with distilled water (100mL×2), 1M NaOH_((aq) ()100 mL×2) and brine (100 mL). The organic layerwas dried over Na₂SO₄, filtered and solvent removed in vacuo to leaveclear yellow oil. The crude product was purified by columnchromatography (ethyl acetate) to give the title compound as a yellowcrystalline solid (12.4 g, 65%),

R_(f): 0.4 (ethyl acetate), c.f. 0.95 (3-bromobenzylbromide);

¹H NMR (270 MHz, CDCl₃) δ 5.27 (2H, s, ArCH₂N), 7.15-7.42 (5H, m, ArH),7.95 (1H, s, C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 52.7 (CH₂), 123.1, 126.5, 130.6, 130.9,131.8, 136.9, 143.2 and 152.4;

HPLC (90% CH₃CN in H₂O) t_(r)=2.273 (100%);

LRMS (FAB⁺), m/z 240.0 (⁸¹BrM⁺+H, 100%), 238.0 (⁷⁹BrM⁺+H, 100);

Anal. Calcd. for C₉H₈BrN₃: C, 45.40; H, 3.39; N, 17.65. Found: C, 45.60;H, 3.55; N, 17.50%.

1-Biphenyl-3-methyl-1H-(1,2,4)-triazole (TJA01006, STX1361)

C₁₅H₁₃N₃ MW 235.28

A 3 necked round bottomed flask was loaded with TJA01009 (0.149 g 0.625mmol), phenylboronic acid (0.738 g, 0.0900 mmol), toluene (9 mL),ethanol (1 mL) and 2M Na₂CO_(3 (aq)) (1 mL). This mixture was degassedby bubbling N_(2 (g)) through it for 1 h. A catalytic quantity ofPd(Ph₃)₄ was added and the reaction mixture heated with vigorousstirring to 115° C. for 20 h. The reaction mixture was allowed to cooland ethyl acetate (100 mL) added. This was then washed with 1MNaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50 mL). Theorganic layer was dried over Na₂SO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified bycolumn chromatography (ethyl acetate) to give a yellow oil thatcrystallised on standing to a waxy yellow solid (R_(f). 0.4).Recrystallisation (cyclohexane) gave the title compound as a whitecrystalline solid (0.0300 g, 20%),

m.p. 81.3-81.5° C.;

R_(f): 0.4 (ethyl acetate), c.f. 0.4(1-biphenyl-3-methyl-1H-(1,2,4)-triazole) and 0.8 (phenylboronic acid);

¹H NMR (270 MHz, CDCl₃) δ 5.40 (2H, s, ArCH₂N), 7.24-7.55 (9H, m, ArH),7.98 (1H, s, C₂H₂N₃) and 8.09 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.7 (CH₂), 126.8, 127.2, 127.5, 127.7,128.9, 129.6, 135.1, 140.4, 142.2, 143.2 and 152.3;

HPLC (90% CH₃CN in H₂O) t_(r)=2.216 (100%);

LCMS (APCI), m/z 236.87 (M⁺+H, 12%), 235.74 (M⁺, 100).

1-(4′-Benzyloxy-biphenyl-3-methyl)-1H-(1,2,4)-triazole (TJA01023,STX1362)

C₂₂H₁₉N₃O MW 341.42

A 3 necked r.b. flask was loaded with TJA01009, (0.119 g 0.500 mmol),4-benzyloxybenzeneboronic acid (0.137 g, 0.600 mmol), potassiumcarbonate (0.173 g, 1.25 mmol), tetrabutylammonium bromide (0.166 g,0.500 mmol) and distilled H₂O (3.5 mL). This mixture was degassed bybubbling N_(2 (g)) through it for 1 h at 70° C. A catalytic quantity ofPd(OAc)₂ (0.006-0.007 g, 2-3 mol %) was added and the reaction mixtureheated with vigorous stirring at 70° C. for 1 h. The reaction mixturewas allowed to cool and ethyl acetate (100 mL) added. This was thenwashed with distilled water (50 mL×3) and brine (50 mL). The organiclayer was dried over Na₂SO₄, filtered and solvent removed in vacuo toleave a yellow solids. The crude product was purified by flashchromatography (20 g column, method10) to give the title compound asyellow solid (0.099 g, 58%),

R_(f): 0.45 (ethyl acetate), c.f. 0.40(1-biphenyl-3-methyl-1H-(1,2,4)-triazole) and 0.8 (3-chlorophenylboronicacid);

¹H NMR (270 MHz, CDCl₃) δ 5.09 (2H, s, ArCH₂O), 5.38 (2H, s, ArCH₂N),7.01-7.04 (2H, d, J=8 Hz, AA′BB′), 7.16-7.19 (1H, m, ArH), 7.31-7.53(10H, m, ArH), 7.97 (1H, s, C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.7 (CH₂), 70.1 (CH₂), 115.3 (C), 126.3,126.4, 127.1, 127.5, 128.1, 128.3, 128.7, 129.5, 133.1, 135.1, 136.8,141.8, 143.1, 152.3 and 158.7;

HPLC (80% CH₃CN in H₂O) t_(r)=2.400 (99.69%);

LCMS (APCI), m/z 341.86 (M⁺+H, 100%), 272.77 ((M⁺+H)—C₂H₂N₃, 40);

HRMS (FAB⁺) calcd. for C₂₂H₁₉N₃O (M)⁺341.1528, found 341.1526.

1-(3′-Chloro-biphenyl-3-yl-methyl)-1H-(1,2,4)-triazole (TJA01018,STX1384)

C₁₅H₁₂ClN₃ MW 269.74

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),3-chlorophenylboronic acid (0.253 g, 2.00 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method1) to give thetitle compound as a clear oil that crystallised on standing to a waxywhite solid (0.219 g, 81%). Recrystallisation (cyclohexane) yielded awhite crystalline solid (0.121 g, 45%),

m.p. 71.8-72.4° C.;

R_(f): 0.45 (ethyl acetate), c.f. 0.40(1-biphenyl-3-methyl-1H-(1,2,4)-triazole) and 0.8 (3-chlorophenylboronicacid)

¹H NMR (270 MHz, CDCl₃) δ 5.39 (2H, s, ArCH₂N), 7.24-7.51 (8H, m, ArH),7.97 (1H, s, C₂H₂N₃) and 8.09 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.5 (CH₂), 125.4, 126.8, 127.3, 127.4,127.5, 127.7, 129.7, 130.1, 134.8, 135.4, 140.8, 142.2, 143.1 and 152.3;

HPLC (60% CH₃CN in H₂O) t_(r)=2.521 (99.04%);

LCMS (APCI), m/z 271.58 (³⁷ClM⁺+H, 35%), 269.2 (³⁵ClM⁺+H, 100), 202.49((³⁷ClM⁺+H)—C₂H₂N₃, 22%), 200.49 ((³⁵ClM⁺+H)—C₂H₂N₃), 60);

HRMS (FAB⁺) calcd. for C₁₅H₁₂N₃C1 (M)⁺269.0720, found 269.0725.

1-(3-Napthalen-biphenyl-2-yl-benzyl)-1H-(1,2,4)-triazole (TJA01019,STX1385)

C₁₉H₁₅N₃ MW 285.35

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),2-naphthaleneboronic acid (0.344 g, 2.00 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method2) to give thetitle compound as a clear yellow oil that crystallised on standing to acream waxy solid (0.165 g, 58%). Recrystallisation (cyclohexane) yieldeda white crystalline solid (0.087 g, 31%),

mp 73.1-75.2° C.;

R_(f): 0.42 (ethyl acetate), c.f. 0.40(1-biphenyl-3-methyl-1H-(1,2,4)-triazole) and 0.75 (2-naphthaleneboronicacid).

¹H NMR (270 MHz, CDCl₃) δ 5.43 (2H, s, ArCH₂N), 7.26 (1H, s, ArH),7.45-7.70 (5H, m, ArH), 7.83-7.91 (3H, m, ArH), 7.99 (1H, s, C₂H₂N₃) and8.11 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.7 (CH₂), 125.4, 126.0, 126.2, 126.5,126.9, 127.1, 127.7, 127.8, 128.2, 128.6, 129.7, 132.8, 133.6, 135.2,137.7, 142.2, 143.2 and 152.3;

HPLC (80% CH₃CN in H₂O) t_(r)=2.466 (99.15%);

LCMS (APCI), m/z 286.19 (M⁺+H, 100%), 217.10 ((M⁺+H)—C₂H₂N₃, 90);

HRMS (FAB⁺) calcd. for C₁₉H₁₅N₃ (M)⁺285.1266, found 285.1253.

1-(4′-Chloro-biphenyl-3-yl-methyl)-1H-(1,2,4)-triazole (TJA01024STX1386)

C₁₅H₁₂ClN₃ MW 269.74

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),4-chlorophenylboronic acid (0.253 g, 2.00 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method2) to give thetitle compound as a clear yellow oil that crystallised on standing to ayellow waxy solid (0.123 g, 46%). Recrystallisation (cyclohexane)yielded a white crystalline solid (0.087 g, 33%),

mp 56.9-59.2° C.;

R_(f): 0.45 (ethyl acetate), c.f. 0.40(1-biphenyl-3-methyl-1H-(1,2,4)-triazole) and 0.80 (2-naphthaleneboronicacid).

¹H NMR (270 MHz, CDCl₃) δ 5.39 (2H, s, ArCH₂N), 7.37-7.50 (8H, m, ArH),7.97 (1H, s, C₂H₂N₃) and 8.09 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.6 (CH₂), 126.6, 127.1, 127.3, 128.4,129.1, 129.7, 135.3, 138.8, 141.0, 143.2 and 152.3 (one overlappingsignal);

HPLC (80% CH₃CN in H₂O) t_(r)=2.401 (98.36%);

LCMS (APCI), m/z 272.02 (³⁷ClM⁺+H, 35%), 270.0 (³⁵ClM⁺+H, 100), 202.91((³⁷ClM⁺+H)—C₂H₂N₃, 21%), 200.491 ((³⁵ClM⁺+H)—C₂H₂N₃, 68);

HRMS (FAB⁺) calcd. for C₁₅H₁₂N₃C1 (M)⁺269.0720, found 269.0733.

3′-(1,2,4)Triazole-1-yl-methyl-biphenyl-4-ol (TJA01025, STX1387)

C₁₅H₁₃N₃O MW 251.29 TJA01022 (0.198 g, 580 mmol) was dissolved in THF (5mL) and MeOH (5 mL) in an r.b. flask to which was added 10% Pd/C (0.015g) to form a black suspension on vigorous stirring. The flask wasevacuated and back filled with H_(2 (g)) via a balloon (×3) and thenleft to stir for 24 h. The reaction mixture was filtered through celitewhich was subsequently washed with THF (30 mL×2). Solvent was removed invacuo to leave a brown residue. Flash chromatography (20 g column,method2) eluted the title compound as a white solid (0.128 g, 88%).Recrystallisation from ethyl acetate/hexane (7:3) gave a whitecrystalline solid (0.0810 g, 56%),

mp 164.4-166.2° C.;

R_(f) 0.44 (ethyl acetate), c.f. 0.50 (TJA01022).

¹H NMR (270 MHz, DMSO-d₆) δ 5.45 (2H, s, ArCH₂N), 6.82-6.85 (2H, d, J=8Hz, AA′BB′), 7.14-7.16 (2H, d, J=7.5 Hz, ArH), 7.35-7.51 (5H, m, ArH),7.98 (1H, s, C₂H₂N₃), 8.69 (1H, s, C₂H₂N₃) and 9.57 (1H, s, ArOH);

¹³C NMR (100 MHz, DMSO-d₆) δ 52.6 (CH₂), 116.2, 126.0, 126.0, 126.3,128.2, 129.6, 130.9, 137.3, 141.0, 144.8, 152.2, 157.8;

HPLC (80% CH₃CN in H₂O) t_(r)=1.820 (100%);

LCMS (APCI), m/z 251.74 (M⁺, 72%), 182.71 (M⁺-C₂H₂N₃, 100).

1-(1,1′,4′,1″)Terphenyl-3-yl-methyl-1H-(1,2,4)triazole (TJA01028, STX1388)

C₂₁H₁₇N₃ MW 311.39

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),4′-biphenylboronic acid (0.297 g, 1.50 mmol), potassium carbonate (0.346g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method2) to give thetitle compound as a yellow solid (0.170 g, 55%),

mp 144.6-147.3° C.;

R_(f): 0.45 (ethyl acetate), c.f. 0.40(1-(3-bromobenzyl)-1H-(1,2,4)-triazole) and 0.80 (4′-biphenylboronicacid).

¹H NMR (270 MHz, CDCl₃) δ 5.41 (2H, s, ArCH₂N), 7.24-7.67 (13H, m, ArH),7.98 (1H, s, C₂H₂N₃) and 8.10 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.7 (CH₂), 126.7, 126.9, 127.1, 127.4,127.5, 127.5, 127.6, 128.9, 129.6, 135.2, 139.2, 140.5, 140.6, 141.7,143.2 and 152.3;

HPLC (80% CH₃CN in H₂O) t_(r)=2.746 (99.28%);

LCMS (APCI), m/z 311.57 (M⁺, 100%), 242.42 (M⁺-C₂H₂N₃, 50).

HRMS (FAB⁺) calcd. for C₂₁H₁₇N₃ (M)⁺ 311.1422, found 311.1477.

1-(4′-Methoxy-biphenyl-3-yl-methyl)-1H-(1,2,4)triazole (TJA01034,STX1452)

C₁₆H₁₅N₃O MW 265.32

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),4-chlorophenylboronic acid (0.253 g, 2.00 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method2) to give thetitle compound as a clear yellow oil that crystallised on standing to ayellow waxy solid (0.129 g, 49%). Recrystallisation (cyclohexane)yielded a white crystalline solid (0.105 g, 39%),

mp 101.5-102.0° C.;

R_(f): 0.5 (ethyl acetate), c.f. 0.40(1-(3-bromobenzyl)-1H-(1,2,4)-triazole) and 0.80 (4′-biphenylboronicacid).

¹H NMR (270 MHz, CDCl₃) δ 3.83 (3H, s, ArOCH₃), 5.38 (2H, s, ArCH₂N),6.94-6.97 (2H, d, J=8.5 Hz, AA′BB′), 7.19 (1H, d, J=7.5 Hz, ArH),7.40-7.50 (5H, m, ArH), 7.97 (1H, s, C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.7 (CH₃), 55.4 (CH₂), 114.3, 126.2,126.4, 127.1, 128.2, 129.5, 132.8, 135.0, 141.8, 143.1, 152.2 and 159.5;

HPLC (80% CH₃CN in H₂O) t_(r)=2.157 (99.21%);

LCMS (APCI), m/z 266.08 (M⁺+H, 100%).

Sulfamic Acid 3′-(1,2,4)triazol-1-ylmethyl-biphenyl-4-yl Ester(TJA01047, STX1455)

C₁₅H₁₄N₄O₃S MW 330.37

Sulfamoyl chloride in toluene (0.35 M, 2.86 mL) was transferred to a 10mL r.b. flask and the solvent removed under vacuum at 30° C. On coolinga white solid formed to which was added N,N-dimethylacetamide (1.5 mL)to form a colourless solution. TJA01025 (0.050 g, 0.199 mmol) was addedand the solution left to stir at room temperature under N_(2 (g)) for 20h. The reaction mixture was then poured into distilled H₂O (30 mL) andextracted with ethyl acetate (25 mL×2). The organic layers were combinedand washed with distilled H₂O (25 mL×4) and brine (25 mL). Dried overNa₂SO₄ and solvent removed in vacuo to leave off white residues. Columnchromatography (dichloromethane/acetone 80:20) eluted the title compoundas an off white waxy solid (0.017 g, 26%);

R_(f) 0.42 (dichloromethane/acetone 80:20), c.f. 0.383′-(1,2,4)triazole-1-yl-methyl-biphenyl-4-ol.

¹H NMR (400 MHz, DMSO-d₆) δ 5.51 (2H, s, ArCH₂N), 7.28-7.30 (1H, d,J=6.5 Hz, ArH), 7.38-7.40 (2H, d, J=9 Hz, AA′BB′), 7.46-7.50 (1H, t,J=7.5 Hz, ArH), 7.60-7.64 (2H, m, ArH), 7.98 (1H, s, C₂H₂N₃), 8.69 (1H,s, C₂H₂N₃) and 9.57 (1H, s, ArOH);

HPLC (80% CH₃CN in H₂O) t_(r)=1.772 min (99.13%);

LCMS (APCI), m/z 330.59 (M⁺, 72%), 261.50 (M⁺-C₂H₂N₃, 100), 182.40((M⁺-C₂H₂N₃) —SO₂NH₂, ⁴⁸);

HRMS (FAB⁺) calcd. for C₁₅H₁₄N₄O₃S (M)⁺330.0787 found 330.0782.

4-Bromo-2-bromomethylbenzonitrile (TJA01043)

C₈H₅Br₂N MW 274.94

4-Bromo-2-methylbenzonitrile (5.00 g, 25.5 mmol), N-bromosuccinimide(4.99 g, 28.1 mmol), benzyl peroxide (0.198 g, 0.816 mmol) and carbontetrachloride (100 mL) were loaded to a r.b. flask and set to reflux(79° C.) for 6 h. Once cooled the succinimide was filtered off andcarbon tetrachloride removed via a dry ice-acetone cooled rotaryevaporator. The residues were dissolved in dichloromethane (100 mL) andwashed with distilled H₂O (50 mL×3) and brine (50 mL×2). Dried overNa₂SO₄ and solvent removed in vacuo to leave yellow residues. Columnchromatography (hexane/dichloromethane 60:40) eluted the title compoundas a yellow solid. Recrystallisation (cyclohexane) gave a whitecrystalline solid (5.07 g, 73%),

mp 61.7-77.2° C.;

R_(f) 0.30 (hexane/dichloromethane 60:40), c.f. 0.36(dibromobenzylbromide), 0.36 (4-bromo-2-methylbenzonitrile);

HPLC (60% CH₃CN in H₂O) R_(t) 3.130 (50.62%), 2.701 (42.38%,dibromobenzylbromide);

MS (EI), m/z 274.0 (M⁻-H, 34%).

4-Bromo-2-(1,2,4)triazol-1-ylmethyl-benzonitrile (TJA01046, STX1454)

C₁₀H₇BrN₄ MW 263.10

TJA01043 (5.00 g, 18.2 mmol), 1,2,4-triazole (1.89 g, 27.3 mmol),potassium carbonate (2.52 g, 18.2 mmol), potassium iodide (0.178 g, 1.07mmol) and acetone (150 mL) were loaded to an r.b. flask. With vigorousstirring this mixture was set to reflux (60° C.) for 4 h. The reactionmixture was allowed to cool and acetone was removed in vacuo. Theresidues were taken up in ethyl acetate (50 mL) and washed withdistilled water (50 mL×2), 1M NaOH (50 mL×1) and brine (50 mL×2). Driedover Na₂SO₄ and solvent removed in vacuo to leave orange/yellowresidues. Flash chromatography (50 g column, method8) eluteddibromobenzylbromide and the title compound as a yellow solid.Recrystallisation (ethyl acetate/hexane 1:6) gave a yellow crystallinesolid (1.58 g, 66%),

mp 106.8-107.6° C.;

R_(f) 0.55 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.51 (2H, s, ArCH₂N), 7.50 (1H, s, ArH),7.53-7.56 (1H, d, J=8.8 Hz, ArH), 7.59-7.62 (1H, dd, J=1.7 & 8.5 Hz,ArH), 7.99 (1H, s, C₂H₂N₃) and 8.27 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 50.7 (CH₂), 110.6, 116.3, 128.8, 132.8,132.9, 134.2, 139.8, 143.9 and 153.0;

HPLC (80% CH₃CN in H₂O) t_(r)=1.947 min (100%);

MS (EI), m/z 264.71 (⁸¹BrM⁺+H, 100%), 262.71. (⁷⁹BrM⁺+H, 99), 195.56((⁸¹BrM⁺+H) —C₂H₂N₃, 81), 193.56 ((⁷⁹BrM⁺+H)—C₂H₂N₃, 80);

Anal. Calc. for C₁₀H₇BrN₄: C, 45.65; H, 2.68; N, 21.30. Found: C, 45.60;H, 2.70; N, 20.9%.

3-[1,2,4]-Triazol-1-ylmethyl-biphenyl-4-carbonitrile (TJA01049, STX1456)

C₁₆H₁₂N₄ MW 260.30

A 3 necked r.b. flask was loaded with TJA01046 (0.100 g 0.380 mmol),phenylboronic acid (0.070 g, 0.570 mmol), potassium carbonate (0.131 g,0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol), distilledH₂O (7 mL) and ethanol (3 mL). This mixture was degassed with N_(2 (g))for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂ (0.002-0.003 g, 2-3mol %) was added and the reaction mixture heated with vigorous stirringto 70° C. for 1 h. The reaction mixture was allowed to cool and ethylacetate (100 mL) added. This was then washed with 1M NaOH_((aq)) (50mL×2), distilled water (50 mL×2) and brine (50 mL). The organic layerwas dried over Na₂SO₄, filtered and solvent removed in vacuo to leave ayellow/brown residue. The crude product was purified by flashchromatography (20 g column, method3) to give the title compound as acolourless oil (0.076 g, 49%). Recrystallisation (cyclohexane) yielded awhite crystalline solid (0.105 g, 39%),

mp 107.8-108.1° C.; R_(f): 0.52 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.59 (2H, s, ArCH₂N), 7.42-7.56 (6H, m, ArH),7.63-7.67 (1H, dd, J=1.8 & 8.1 Hz, ArH), 7.74-7.77 (1H, d, J=8.2 Hz,ArH), 7.98 (1H, s, C₂H₂N₃) and 8.30 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 51.4 (CH₂), 110.3, 117.1, 127.3, 127.8,128.2, 129.1, 129.2, 133.6, 138.4, 138.6, 143.9, 146.7 and 152.8;

HPLC (90% CH₃CN in H₂O) t_(r)=2.034 (100%);

LCMS (APCI), m/z 261.18 (M⁺+H, 100%), 191.99 ((M⁺+H)—C₂H₂N₃, 15).

4-Benzyloxy-3-[1,2,4]triazol-1-ylmethyl-biphenyl-4-carbonitrile(TJA01050, STX1457)

C₂₃H₁₈N₄O MW 366.43

A 3 necked r.b. flask was loaded with TJA01046 (0.300 g 1.14 mmol),4-benzyloxybenzene boronic acid (0.390 g, 1.71 mmol), potassiumcarbonate (0.390 g, 2.85 mmol), tetrabutylammonium bromide (0.379 g,1.14 mmol), distilled H₂O (7 mL) and ethanol (3 mL). This mixture wasdegassed with N_(2 (g)) for 1 h at 70° C. A catalytic quantity ofPd(OAc)₂ (0.002-0.003 g, 2-3 mol %) was added and the reaction mixtureheated with vigorous stirring to 70° C. for 1 h. The reaction mixturewas allowed to cool and ethyl acetate (100 mL) added. This was thenwashed with 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) andbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered andsolvent removed in vacuo to leave a yellow/brown residue. The crudeproduct was purified by flash chromatography (20 g column, method3) togive the title compound as a pale yellow solid (0.315 g, 75%).Precipitation (EtOAc/hexane) yielded a white solid (0.270 g, 65%),

mp 127.7-128.1° C.;

R_(f): 0.52 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.10 (2H, s, ArOCH₂), 5.58 (2H, s, ArCH₂N),7.02-7.05 (2H, d, J=11.5 Hz, AA′BB′), 7.32-7.51 (8H, m, ArH), 7.58-7.61(1H, d, J=8.0 Hz, ArH), 7.70-7.73 (1H, d, J=8.0 Hz, ArH), 7.98 (1H, s,C₂H₂N₃) and 8.28 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 51.4 (CH₂), 70.1 (CH₂), 109.5, 115.6,117.3, 127.2, 127.5, 127.6, 128.2, 128.5, 128.7, 131.0, 133.6, 136.5,138.5, 143.8, 146.1, 152.7 and 159.7;

HPLC (80% CH₃CN in H₂O) t_(r)=2.276 (99.82%);

LCMS (APCI), m/z 367.29 (M⁺+H, 100%).

3′-[1,2,4]-Triazol-1-ylmethyl-biphenyl-3-carbonitrile (TJA01051,STX1458)

C₁₆H₁₂N₄ MW 260.30

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),3-cyanophenyl boronic acid (0.220 g, 1.50 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method3) to give thetitle compound as a viscous colourless oil (0.190 g, 73%),

R_(f): 0.30 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.36 (2H, s, ArCH₂N), 7.22-7.26 (1H, dt, J=1.5& 9.0 Hz, ArH), 7.38-7.51 (4H, m, ArH), 7.56-7.60 (1H, dt, J=1.5 & 7.5Hz, ArH), 7.67-7.71 (1H, dt, J=1.5 & 7.7 Hz, ArH), 7.75-7.76 (1H, m,ArH), 7.93 (1H, s, C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.4 (CH₂), 113.1, 118.7, 126.7, 127.5,127.9, 129.8, 130.0, 130.8, 131.2, 131.6, 135.7, 139.9, 141.6, 143.2 and152.4;

HPLC (80% CH₃CN in H₂O) t_(r)=2.013 (100%);

LCMS (APCI), m/z 261.18 (M⁺+H, 82%), 191.99 ((M⁺+H)—C₂H₂N₃, 100).

3′-[1,2,4]-Triazol-1-ylmethyl-biphenyl-4-carbonitrile (TJA01054,STX1459)

C₁₆H₁₂N₄ MW 260.30

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g 1.00 mmol),4-cyanophenyl boronic acid (0.220 g, 1.50 mmol), potassium carbonate(0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g, 1.00 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a viscous colourless oil that crystallised on standingto give a white crystalline solid (0.190 g, 73%),

mp 117.4-117.9° C.;

R_(f): 0.38 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.38 (2H, s, ArCH₂N), 7.28-7.31 (1H, m, ArH),7.44-7.57 (3H, m, ArH), 7.62-7.74 (4H, dd, J=2.0 & 8.5 Hz, AA′BB′), 7.97(1H, s, C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.4 (CH₂), 111.4, 118.8, 126.8, 127.6,127.8, 128.1, 129.9. 132.7, 135.8, 140.2, 143.2, 144.8 and 152.4;

HPLC (80% CH₃CN in H₂O) t_(r)=1.990 (98.29%);

LCMS (APCI), m/z 261.18 (M⁺+H, 100%), 191.99 ((M⁺+H)—C₂H₂N₃, 88).

1-(4′-Benzyloxy-3′-chloro-biphenyl-3-ylmethyl)-1H-(1,2,4)triazole(TJA01055-1, STX1502)

C₂₂H₁₈ClN₃O MW 375.11

A 3 necked r.b. flask was loaded with TJA01009 (0.250 g 1.05 mmol),4-benzyloxy-3-chlorophenylboronic acid (0.413 g, 1.58 mmol), potassiumcarbonate (0.363 g, 2.63 mmol), tetrabutylammonium bromide (0.349 g,1.05 mmol), distilled H₂O (7 mL) and ethanol (3 mL). This mixture wasdegassed with N_(2 (g)) for 1 h at 70° C. A catalytic quantity ofPd(OAc)₂ (0.006-0.007 g, 2-3 mol %) was added and the reaction mixtureheated with vigorous stirring to 70° C. for 1 h. The reaction mixturewas allowed to cool and ethyl acetate (100 mL) added. This was thenwashed with 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) andbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered andsolvent removed in vacuo to leave a yellow/brown residue. The crudeproduct was purified by flash chromatography (20 g column, method4) togive the title compound as a white crystalline solid (0.150 g, 38%),

mp 91.2-91.8° C.;

R_(f): 0.40 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.19 (2H, s, ArOCH₂), 5.38 (2H, s, ArCH₂N),6.98-7.01 (1H, d, J=8.6 Hz, ArH), 7.18-7.50 (9H, m, ArH), 7.57-7.58 (1H,d, J=2.2 Hz, ArH)), 7.97 (1H, s, C₂H₂N₃) and 8.08 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.6 (CH₂), 70.9 (CH₂), 114.2, 123.7,126.3, 126.4, 126.8, 127.1, 128.1, 128.7, 129.0, 129.7, 134.1, 135.3,136.4, 140.5, 143.2, 152.3 and 153.9 (one overlapping signal);

HPLC (80% CH₃CN in H₂O) t_(r)=2.573 (99.33%);

LCMS (APCI), m/z 378.19 (³⁷ClM⁺+H, 30%), 379.24 (³⁵ClM⁺+H, 100).

3′Chloro-3-(1,2,4)triazol-1-ylmethyl-biphenyl-4-carbonitrile(TJA01055-2, STX1503)

C₁₆H₁₁ClN₄ MW 294.07

A 3 necked r.b. flask was loaded with TJA01046 (0.100 g, 0.380 mmol),3-chlorophenylboronic acid (0.089 g, 0.570 mmol), potassium carbonate(0.131 g, 0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a yellow waxy solid (0.076 g, 68%),

mp 107.8-108.2° C.;

R_(f): 0.46 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.59 (2H, s, ArCH₂N), 7.38 (3H, d, J=1.5 Hz,ArH), 7.49-7.64 (3H, m, ArH), 7.75-7.77 (1H, d, J=7.9 Hz, ArH)), 7.98(1H, s, C₂H₂N₃) and 8.31 (1H, S, C₂H₂N₃);

¹³NMR (100.5 MHz, CDCl₃) δ 51.3 (CH₂), 111.0, 116.9, 125.5, 127.4,127.9, 128.3, 129.1, 130.5, 133.7, 135.2, 138.8, 140.2, 143.9, 145.2 and152.8;

HPLC (80% CH₃CN in H₂O) t_(r)=2.136 (95.08%);

LCMS (APCI), m/z 297.26 (³⁷ClM⁺+H, 30%), 295.25 (³⁵ClM⁺+H, 100).

4-Naphthalene-2-yl-2-(1,2,4)triazol-1-ylmethyl-benzonitrile (TJA01055-3,STX1504)

C₂₀H₁₄N₄ MW 310.35

A 3 necked r.b. flask was loaded with TJA01046 (0.100 g, 0.380 mmol),2-naphthaleneboronic acid (0.098 g, 0.570 mmol), potassium carbonate(0.131 g, 0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a yellow solid (0.061 g, 52%),

mp 119.1-120.8° C.;

R_(f): 0.47 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.61 (2H, s, ArCH₂N), 7.49-7.98 (10H, m, ArH),7.99 (1H, s, C₂H₂N₃) and 8.32 OK s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 51.4 (CH₂), 110.3, 117.2, 124.7, 126.8,126.9, 127.1, 127.8, 128.4, 128.5, 129.1, 133.3, 133.4, 133.7, 135.7,138.6, 143.9, 146.6, and 152.8;

HPLC (80% CH₃CN in H₂O) t_(r)=2.224 (99.00%);

LCMS (APCI), m/z 311.24 (M⁺+H, 100%).

3′-(1,2,4)Triazol-1-ylmethyl-biphenyl-3,4′-dicarbonitrile (TJA01055-4,STX1505)

C₁₇H₁₁N₅ MW 285.10

A 3 necked r.b. flask was loaded with TJA01046 (0.100 g, 0.380 mmol),3-cyanophenylboronic acid (0.084 g, 0.570 mmol), potassium carbonate(0.131 g, 0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a white solid (0.066 g, 61%),

mp 160.4-160.8° C.;

R_(f): 0.35 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.60 (2H, s, ArCH₂N), 7.36-7.81 (7H, m, ArH),7.97 (1H, s, C₂H₂N₃) and 8.32 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 51.2 (CH₂), 111.6, 113.6, 116.7, 118.2,127.9, 128.4, 130.2, 130.8, 131.6, 132.4, 133.9, 139.1, 139.8, 143.9,144.2 and 152.9;

HPLC (80% CH₃CN in H₂O) t_(r)=1.907 (100%);

LCMS (APCI), m/z 286.30 (M⁺+H, 100%).

2-Methyl-2-(5-(1,2,4)triazol-1-ylmethyl-biphenyl-3-yl)-propionitrile(TJA01055-5, STX1506)

C₁₉H₁₈N₄ MW 302.15

A 3 necked r.b. flask was loaded with TJA01037 (0.100 g, 0.328 mmol),phenylboronic acid (0.060 g, 0.492 mmol), potassium carbonate (0.113 g,0.820 mmol), tetrabutylammonium bromide (0.109 g, 0.328 mmol), distilledH₂O (3.5 mL) and ethanol (1.5 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a yellow viscous oil (0.065 g, 66%),

R_(f): 0.27 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 1.67 (6H, s, ArC(CH₃)₂CN), 5.35 (2H, s,ArCH₂N), 7.23-7.47 (7H, m, ArH), 7.56-7.57 (1H, t, J=1.8 Hz, ArH), 7.92(1H, s, C₂H₂N₃) and 8.08 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 29.2 (CH₃), 37.3 (C), 53.4 (CH₂), 123.4,124.2, 124.4, 126.6, 127.3, 128.1, 129.0, 136.1, 139.8, 143.0, 143.2,143.3 and 152.5;

HPLC (80% CH₃CN in H₂O) t_(r)=2.062 (97.56%); LCMS (APCI), m/z 303.31(M⁺+H, 100%), 234.17 ((M⁺+H)—C₂H₂N₃, 30%).

2-(3′-Chloro-5-(1,2,4)triazol-1-ylmethyl-biphenyl-3-yl)-2-methyl-propionitrile(TJA01055-6, STX1507)

C₁₉H₁₇ClN₄ MW 336.11

A 3 necked r.b. flask was loaded with TJA01037 (0.100 g, 0.328 mmol),3-chlorophenylboronic acid (0.077 g, 0.492 mmol), potassium carbonate(0.113 g, 0.820 mmol), tetrabutylammonium bromide (0.109 g, 0.328 mmol),distilled H₂O (3.5 mL) and ethanol (1.5 mL). This mixture was degassedwith N_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a colourless viscous oil (0.077 g, 70%),

R_(f): 0.31 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 1.73 (6H, s, ArC(CH₃)₂CN), 5.40 (2H, s,ArCH₂N), 7.29-7.38 (5H, m, ArH), 7.46-7.48 (1H, dd, J=1.4 & 1.5 Hz,ArH), 7.57-7.58 (1H, t, J=1.7 Hz, ArH), 7.98 (1H, s, C₂H₂N₃) and 8.14(1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 29.2 (CH₃), 37.3 (C), 53.3 (CH₂), 124.0,124.4, 125.5, 126.3, 127.4, 128.2, 130.3, 134.9, 136.4, 141.7, 141.8,143.2, 143.3 and 152.5 (one overlapping signal);

HPLC (80% CH₃CN in H₂O) t_(r)=2.190 (95.03%);

LCMS (APCI), m/z 339.27 (³⁷ClM⁺+H, 42%), 337.25 (³⁵ClM⁺+H, 100), 270.25((³⁷ClM⁺+H)—C₂H₂N₃, 10) 268.17 ((³⁵ClM⁺+H)—C₂H₂N₃, 30).

2-Methyl-2(3-naphthalene-2-yl-5-(1,2,4)triazol-1-ylmethyl-phenyl)-propionitrile(TJA01055-7, STX1508)

C₂₃H₂₀N₄ MW 352.17

A 3 necked r.b. flask was loaded with TJA01037 (0.100 g, 0.328 mmol),2-naphthaleneboronic acid (0.085 g, 0.492 mmol), potassium carbonate(0.113 g, 0.820 mmol), tetrabutylammonium bromide (0.109 g, 0.328 mmol),distilled H₂O (3.5 mL) and ethanol (1.5 mL). This mixture was degassedwith N_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a pale yellow waxy solid (0.061 g, 53%),

R_(f): 0.31 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 1.72 (6H, s, ArC(CH₃)₂CN), 5.40 (2H, s,ArCH₂N), 7.32-7.49 (4H, m, ArH), 7.57-7.60 (1H, dd, J=2.0 & 6.7 Hz,ArH), 7.70-7.71 (1H, t, J=1.7 Hz, ArH), 7.78-7.91 (4H, m, ArH), 7.95(1H, s, C₂H₂N₃) and 8.11 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 29.2 (CH₃), 37.3 (C), 53.4 (CH₂), 109.9,123.5, 124.2, 124.7, 125.3, 126.2, 126.5, 126.6, 126.7, 127.7, 128.3,128.8, 132.9, 133.5, 136.2, 137.1, 143.1, 143.3 and 152.5; HPLC (80%CH₃CN in H₂O) t_(r)=2.251 (98.56%);

LCMS (APCI), m/z 353.37 (M⁺+H, 100%), 284.29 ((M⁺+H)—C₂H₂N₃, 35).

3′-(Cyano-dimethyl-methyl)-5′-(1,2,4)triazol-1-ylmethyl-biphenyl-3-carbonitrile(TJA01055-8, STX1509)

C₂₀H₁₇N₅ MW 327.15

A 3 necked r.b. flask was loaded with TJA01037 (0.100 g, 0.328 mmol),3-cyanophenylboronic acid (0.072 g, 0.492 mmol), potassium carbonate(0.113 g, 0.820 mmol), tetrabutylammonium bromide (0.109 g, 0.328 mmol),distilled H₂O (3.5 mL) and ethanol (1.5 mL). This mixture was degassedwith N_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a yellow viscous oil (0.038 g, 36%),

R_(f): 0.23 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 1.70 (6H, s, ArC(CH₃)₂CN), 5.38 (2H, s,ArCH₂N), 7.30-7.74 (7H, m, ArH), 7.93 (1H, s, C₂H₂N₃) and 8.12 (1H, s,C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 29.1 (CH₃), 37.3 (C), 53.1 (CH₂), 113.3,118.5, 123.9, 124.4, 124.5, 126.2, 129.9, 130.8, 131.5, 131.7, 136.8,140.9, 141.1, 143.4, 143.6 and 152.5;

HPLC (80% CH₃CN in H₂O) t_(r)=1.910 (100%);

LCMS (APCI), m/z 328.31 (M⁺+H, 100%), 259.17 ((M⁺+H)—C₂H₂N₃, 22).

3-(1,2,4)Triazol-1-ylmethyl-biphenyl-4,4′-dicarbonitrile (TJA01055-9,STX1510)

C₁₇H₁₁N₅ MW 285.10

A 3 necked r.b. flask was loaded with TJA01046 (0.100 g, 0.380 mmol),4-cyanophenylboronic acid (0.084 g, 0.570 mmol), potassium carbonate(0.131 g, 0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.002-0.003 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a white solid (0.082 g, 76%),

mp 222.1-222.6° C.

R_(f): 0.36 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.56 (2H, s, ArCH₂N), 7.52-7.77 (7H, m, ArH),7.94 (1H, s, C₂H₂N₃) and 8.27 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.1 (CH₂), 111.8, 112.8, 116.6, 118.3,128.0, 128.4, 133.0, 133.9, 139.1, 142.8, 144.0, 144.6 and 152.9;

HPLC (80% CH₃CN in H₂O) t_(r)=1.908 (100%);

LCMS (APCI), m/z 286.24 (M⁺+H, 100%).

Phenyl-(3′-(1,2,4)triazol-1-ylmethyl-biphenyl-3-yl)-methanone(TJA01055-10, STX1511)

C₂₂H₁₇N₃O MW 339.14

A 3 necked r.b. flask was loaded with TJA01009 (0.100 g, 0.420 mmol),4-benzoylphenylboronic acid (0.142 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),distilled H₂O (7 mL) and ethanol (3 mL). This mixture was degassed withN_(2 (g)) for 1 h at 70° C. A catalytic quantity of Pd(OAc)₂(0.006-0.007 g, 2-3 mol %) was added and the reaction mixture heatedwith vigorous stirring to 70° C. for 1 h. The reaction mixture wasallowed to cool and ethyl acetate (100 mL) added. This was then washedwith 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) and brine (50mL). The organic layer was dried over Na₂SO₄, filtered and solventremoved in vacuo to leave a yellow/brown residue. The crude product waspurified by flash chromatography (20 g column, method4) to give thetitle compound as a white solid (0.071 g, 50%),

mp 120.7-120.9° C.;

R_(f): 0.24 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.41 (2H, s, ArCH₂N), 7.25-7.28 (1H, m, ArH),7.43-7.64 (8H, m, ArH), 7.77-7.86 (4H, m, ArH), 7.97 (1H, s, C₂H₂N₃) and8.12 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 52.0 (CH₂), 126.9, 127.1, 127.7, 128.4,129.8, 130.1, 132.5, 135.5, 136.7, 137.6, 141.0, 143.2, 144.3, 152.4 and196.3 (three overlapping signals);

HPLC (80% CH₃CN in H₂O) t_(r)=2.297 (96.90%);

LCMS (APCI), m/z 340.34 (M⁺+H, 100%), 271.19 ((M⁺+H)—C₂H₂N₂, 41).

1-(3′-Chloro-4-methoxy-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole(TJA01061, STX1512)

C₁₆H₁₄ClN₃O MW 299.75

A 3 necked r.b. flask was loaded with TJA01009 (0.238 g, 1.00 mmol),3-chloro-4-methoxyphenylboronic acid (0.280 g, 1.50 mmol), potassiumcarbonate (0.346 g, 2.50 mmol), tetrabutylammonium bromide (0.332 g,1.00 mmol), distilled H₂O (7 mL) and ethanol (3 mL). This mixture wasdegassed with N_(2 (g)) for 1 h at 70° C. A catalytic quantity ofPd(OAc)₂ (0.006-0.007 g, 2-3 mol %) was added and the reaction mixtureheated with vigorous stirring to 70° C. for 1 h. The reaction mixturewas allowed to cool and ethyl acetate (100 mL) added. This was thenwashed with 1M NaOH_((aq)) (50 mL×2), distilled water (50 mL×2) andbrine (50 mL). The organic layer was dried over Na₂SO₄, filtered andsolvent removed in vacuo to leave a yellow/brown residue. The crudeproduct was purified by flash chromatography (20 g column, method4) togive the title compound as a pale yellow solid (0.187 g, 63%),

mp 78.2-78.4° C.;

R_(f): 0.21 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 3.87 (3H, s, ArOCH₃), 5.32 (2H, s, ArCH₂N),6.90-6.93 (1H, d, J=8.4 Hz, ArH), 7.13-7.51 (6H, m, ArH), 7.92 (1H, s,C₂H₂N₃) and 8.04 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.6, 56.3, 112.3, 122.9, 126.4, 126.8,127.1, 128.9, 129.7, 133.7, 135.3, 140.5, 143.2, 152.3 and 154.7;

HPLC (80% CH₃CN in H₂O) t_(r)=2.188 (99.43%);

LCMS (APCI), m/z 302.24 (³⁷ClM⁺+H, 52%), 300.22 (³⁵ClM⁺+H, 82), 233.10((³⁷ClM⁺+H)—C₂H₂N₃, 78), 231.09 ((³⁵ClM⁺+H)—C₂H₂N₃, 100).

3-Chloro-3-[1,2,4]triazol-1-ylmethyl-biphenyl-4-ol (TJA01064, STX1519)

C₁₅H₁₂ClN₃O MW 285.73

TJA01055-1 (0.100 g, 0.267 mmol) was dissolved in THF (5 mL) and MeOH (5mL) in an r.b. flask to which was added 10% Pd/C (0.010 g) to form ablack suspension on vigorous stirring. The flask was evacuated and backfilled with H_(2 (g)) via a balloon (×3) and then left to stir for 16 h.The reaction mixture was filtered through celite which was subsequentlywashed with THF (30 mL×2). Solvent was removed in vacuo to leave a brownresidue. Flash chromatography (20 g column, method5) eluted the titlecompound as a white solid (0.051 g, 67%),

mp 153.2-153.3° C.

R_(f): 0.28 (ethyl acetate).

¹H NMR (270 MHz, DMSO-d₆) δ 5.54 (2H, s, ArCH₂N), 7.03-7.06 (1H, d,J=8.4 Hz, ArH), 7.17-7.20 (1H, d, J=7.4 Hz, ArH), 7.36-7.45 (2H, m,ArH), 7.54-7.56 (2H, d, J=7.2 Hz, ArH), 7.60-7.61 (1H, d, J=2.5 Hz,ArH), 7.99 (1H, s, C₂H₂N₃), 8.70 (1H, s, C₂H₂N₃) and 10.36 (1H, s,ArOH); HPLC (80% CH₃CN in H₂O) t_(r)=1.982 (95.50%); LCMS (APCI), m/z286.18 (³⁷ClM⁻-H, 30%), 284.16 (³⁵ClM⁻-H, 100).

4′-Hydroxy-3-[1,2,4]triazol-1-ylmethyl-biphenyl-4-carbonitrile(TJA01065, STX1520)

C₁₆H₁₂N₄O MW 276.30

A 10 mL microwave vial was loaded with TJA01046 (0.100 g, 0.380 mmol),4-hydroxyphenylboronic acid (0.079 g, 0.570 mmol), potassium carbonate(0.131 g, 0.950 mmol), tetrabutylammonium bromide (0.126 g, 0.380 mmol),Pd(OAc)₂ (0.001-0.002 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 mm at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over Na₂SO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a white solid (0.082 g, 79%),

mp 203.4-203.6° C.

R_(f): 0.43 (ethyl acetate).

¹H NMR (270 MHz, DMSO-d₆) δ 5.62 (2H, s, ArCH₂N), 6.85-6.88 (2H, d,j=8.7 Hz, ArH), 7.51-7.55 (2H, d, J=8.7 Hz, ArH), 7.67-7.89 (3H, m,ArH), 7.99 (1H, s, C₂H₂N₃), 8.71 (1H, s, C₂H₂N₃) and 9.83 (1H, s, ArOH);

¹³C NMR (100.5 MHz, DMSO-d₆) δ 51.0, 109.2, 116.5, 117.8, 126.5, 127.5,128.8, 134.3, 139.9, 145.4, 152.6 and 159.0;

HPLC (80% CH₃CN in H₂O) t_(r)=1.783 (97.91%);

LCMS (APCI), m/z 275.22 (M⁺+H, 100%).

2-(4′-Hydroxy-5-[1,2,4]-triazol-1-ylmethyl-biphenyl-3-yl)-2-methyl-propionitrile(TJA01067, STX1521)

C₁₉H₁₈N₄O Mw 318.37

A 10 mL microwave vial was loaded with TJA01037 (0.200 g, 0.656 mmol),4-hydroxyphenylboronic acid (0.136 g, 0.984 mmol), potassium carbonate(0.227 g, 1.64 mmol), tetrabutylammonium bromide (0.218 g, 0.656 mmol),Pd(OAc)₂ (0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30×3 mL) and brine (30 mL).The organic layer was dried over Na₂SO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a pale yellow (0.216 g, 89%),

mp 65.8-68.1° C.

R_(f): 0.28 (ethyl acetate).

¹H NMR (270 MHz, DMSO-d₆) δ 1.71 (6H, s, ArC(CH₃)₂CN), 5.49 (2H, s,ArCH₂N), 6.84-6.87 (2H, d, J=8.7 Hz, ArH), 7.38 (1H, s, ArH), 7.42 (1H,s, ArH), 7.44-7.48 (2H, d, J=8.7 Hz, ArH), 7.59 (1H, s, ArH), 8.00 (1H,s, C₂H₂N₃), 8.72 (1H, s, C₂H₂N₃) and 9.64 (1H, s, ArOH);

¹³C NMR (100.5 MHz, DMSO-d₆) δ 28.8 (CH₃), 37.3 (C), 52.5 (CH₂), 116.3,122.9, 123.3, 125.0, 125.5, 128.5, 130.5, 138.0, 141.8, 143.0, 144.9,152.3 and 158.0;

HPLC (80% CH₃CN in H₂O) t_(r)=1.787 (99.55%);

LCMS (APCI), m/z 317.29 (M⁻-H, 100%).

1-(3′-Fluoro-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole (TJA01070, STX1524)

C₁₅H₁₂FN₃ MW 253.27

A 10 mL microwave vial was loaded with TJA01009 (0.100 g, 0.420 mmol),3-fluorophenylboronic acid (0.088 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C.complete conversion was evident by tlc (ethyl acetate). The reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a colourless oil (0.035 g, 30%),

R_(f): 0.29 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.39 (2H, s, ArCH₂N), 7.02-7.06 (1H, s, ArH),7.20-7.54 (7H, m, ArH), 7.97 (1H, s, C₂H₂N₃) and 8.09 (1H, s, C₂H₂N₃);

HPLC (80% CH₃CN in H₂O) t_(r)=2.151 (96.90%);

LCMS (APCI), m/z 254.13 (M⁺+H, 62%), 184.94 ((M⁺+H)—C₂H₂N₃, 100).

1-(4′-Fluoro-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole (TJA01071, STX1525)

C₁₅H₁₂FN₃ MW 253.27

A 10 mL microwave vial was loaded with TJA01009 (0.100 g, 0.420 mmol),4-fluorophenylboronic acid (0.088 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C.complete conversion was evident by tlc (ethyl acetate). The reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas an off white solid (0.030 g, 28%),

mp 82.9-83.8° C.;

R_(f): 0.32 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.34 (2H, s, ArCH₂N), 7.02-7.08 (2H, m, ArH),7.15-7.19 (1H, d, J=7.6 Hz, ArH), 7.35-7.46 (5H, m, ArH), 7.92 (1H, s,C₂H₂N₃) and 8.04 (1H, s, C₂H₂N₃);

¹³C NMR (100.5 MHz, CDCl₃) δ 53.6 (CH₃), 115.7-115.9 (J_(C-F) 21.5 Hz),126.7, 126.8, 127.4, 128.7-128.8 (J_(C-F) 8.5 Hz), 129.6, 135.3, 136.5,141.2, 143.2, 152.3 and 161.5-163.9 (J_(C-F) 246.9 Hz);

HPLC (80% CH₃CN in H₂O) t_(r)=2.168 (98.68%);

LCMS (APCI), m/z 254.19 (M⁺+H, 48%), 185.07 ((M⁺+H)—C₂H₂N₃, 100).

1-(2′-Phenoxy-biphenyl-3-ylmethyl)-1H-1,2,41-triazole (TJA01135,STX1835)

C₂₁H₁₇N₃O MW 327.38

A 10 mL microwave vial was loaded with TJA01009 (0.100 g, 0.420 mmol),4-phenoxyphenylboronic acid (0.135 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a light yellow viscous oil (0.120 g, 88%),

R_(f): 44 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.41 (2H, s, ArCH₂N), 6.83-6.86 (2H, d,J=7.7 Hz, ArH), 6.98-7.05 (2H, m, ArH), 7.19-7.51 (11H, m, ArH), 7.97(1H, s, C₂H₂N₃) and 8.63 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.7, 117.9, 120.1, 120.4, 122.8, 124.3,126.9, 129.0, 129.2, 129.6, 129.7, 131.2, 132.9, 134.4, 138.7, 143.1,152.2, 153.5 and 157.7; HPLC (90% CH₃CN in H₂O) t_(r)=2.278 (98.66%);

LCMS (APCI), m/z 328.46 (M⁺+H, 100%);

1-(3′-[1,2,4]Triazol-1-ylmethyl-biphenyl-3-yl)-ethanone (TJA01136,STX1838)

C₁₇H₁₅N₃O MW 277.32

A 10 mL microwave vial was loaded TJA01009 (0.100 g, 0.420 mmol),3-acetylphenylboronic acid (0.103 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a colourless viscous oil (0.074 g, 64%),

R_(f): 0.38 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 2.62 (3H, s, ArCOCH₃), 5.42 (2H, s, ArCH₂N),7.28 (1H, s, ArH), 7.41-7.62 (4H, m, ArH), 7.71-7.76 (1H, ddd, J=0.7 &2.0 & 11.0 Hz, ArH), 7.92-7.94 (1H, dt, J=0.5 & 7.7 Hz, ArH), 7.98 (1H,s, C₂H₂N₃), 8.11 (1H, s, C₂H₂N₃) and 8.13-8.15 (1H, t, J=1.8 Hz, ArH);

¹³C NMR (100.5 MHz, CDCl₃) δ 26.9 (CH₃), 53.6 (CH₂), 126.9 (CH), 127.4(CH), 127.7 (CH), 127.8 (CH), 129.3 (CH), 129.8 (CH), 131.9 (CH), 135.5(C), 137.7 (C), 140.9 (C), 141.2 (C), 143.3 (CH), 152.4 (CH) and 198.1(C═O) (one overlapping signal); HPLC (90% CH₃CN in H₂O) t_(r)=2.300(100%);

LCMS (APCI), m/z 278.39 (M⁺+H, 100%).

STX1839

1-(3-Dibenzofuran-4-yl-benzyl)-1H-[1,2,4]-triazole (TJA01137, STX1839)

C₂₁H₁₅N₃O MW 325.36

A 10 mL microwave vial was loaded with TJA01009 (0.100 g, 0.420 mmol),4-dibenzofuranboronic acid (0.134 g, 0.630 mmol), potassium carbonate(0.145 g, 1.05 mmol), tetrabutylammonium bromide (0.139 g, 0.420 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a colourless viscous oil (0.097 g, 71%),

R_(f): 0.39 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.47 (2H, s, ArCH₂N), 7.28-7.60 (7H, m, ArH),7.81 (1H, m, ArH), 7.87-7.99 (3H, m, ArH), 8.04 (1H, s, C₂H₂N₃) and 8.16(1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.8 (CH₂), 111.9 (CH), 120.2 (CH), 120.8(CH), 123.0 (CH), 123.4 (CH), 124.1 (C), 125.0 (C), 125.1 (C), 126.8(CH), 127.4 (CH), 127.5 (CH), 128.5 (CH), 129.2 (CH), 129.5 (CH), 135.1(C), 137.4 (C), 143.3 (CH), 152.4 (CH), 153.3 (C) and 156.1 (C); HPLC(90% CH₃CN in H₂O) t_(r)=3.018 (98.25%);

LCMS (APCI), m/z 326.45 (M⁺+H, 100%).

3′-[1,2,4]Triazol-1-ylmethyl-biphenyl-3-ol (TJA01138, STX1840)

C₁₅H₁₃N₃O MW 251.29

A 10 mL microwave vial was loaded with TJA01009 (0.150 g, 0.630 mmol),3-hydroxyphenylboronic acid (0.130 g, 0.945 mmol), potassium carbonate(0.218 g, 1.58 mmol), tetrabutylammonium bromide (0.209 g, 0.630 mmol),Pd(OAc)₂ (0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (25×3 mL) and brine (25 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method4) eluting the title compoundas a pale yellow solid (0.130 g, 82%),

R_(f): 0.25 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.48 (2H, s, ArCH₂N), 6.75-6.79 (1H, dd,J=0.8 & 8.9 Hz, ArH), 6.97-7.04 (2H, m, ArH), 7.23-7.29 (2H, m, ArH),7.43-7.58 (3H, m, ArH), 8.01 (1H, s, C₂H₂N₃), 8.73 (1H, s, C₂H₂N₃) and9.59 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.6 (CH₂), 114.0 (CH), 115.2 (CH), 118.0(CH), 126.7 (CH), 127.4 (CH), 129.8 (CH), 130.6 (CH), 137.5 (C), 141.2(C), 141.7 (C), 144.9 (CH), 152.4 (CH) and 158.4 (C) (one overlappingsignal);

HPLC (90% CH₃CN in H₂O) t_(r)=2.199 (99.70%);

LCMS (APCI), m/z 252.25 (M⁺+H, 100%);

4-Bromo-2-bromomethyl-1-fluoro-benzene (TJA01131)

C₇H₅Br₂F MW 267.92

5-bromo-2-fluorotoluene (5.00 g, 26.5 mmol), N-bromosuccinimide (5.18 g,29.1 mmol), benzyl peroxide (0.205 g, 0.850 mmol) and carbontetrachloride (50 mL) were loaded to a r.b. flask and set to reflux (79°C.) for 2 h. Once cooled the succinimide was filtered off and carbontetrachloride removed via a dry ice-acetone cooled rotary evaporator.The residues were dissolved in dichloromethane (100 mL) and washed withdistilled H₂O (50 mL×3) and brine (50 mL). Dried over MgSO₄ and solventremoved in vacuo to yield the title compound as a colourless liquidyellow (6.80 g, 96%),

R_(f): 0.55 (dichloromethane/hexane 10:90), c.f. 0.79(5-bromo-2-fluorotoluene); HPLC (70% CH₃CN in H₂O) t_(r)=4.786 (71.55%);

1-(5-Bromo-2-fluoro-benzyl)-1H-[1,2,4]triazole (TJA01132, STX1834)

C₉H₇BrFN₃ MW 256.07

To a solution of TJA01131 (5.00 g, 18.7 mmol) in acetone (50 mL) wasadded 1,2,4-triazole (1.94 g, 28.1 mmol), potassium carbonate (2.58 g,18.7 mmol) and potassium iodide (0.182 g, 1.10 mmol). The resultingwhite suspension was heated to 55° C. with vigorous stirring for 16 h.The yellow reaction mixture was cooled and ethyl acetate (100 mL) added.This was then washed with distilled water (100 mL×2) and brine (100 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave clear yellow oil that crystallises on standing to givethe title compound as a yellow crystalline solid (2.54 g, 53%),

R_(f): 0.57 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.33 (2H, s, ArCH₂N), 6.94-7.01 (1H, t, J=8.9Hz, ArH), 7.34-7.44 (2H, m, ArH), 7.95 (1H, s, C₂H₂N₃) and 8.14 (1H, s,C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 46.8 (CH₂), 117.2-117.3 (C, J_(C-F) 3.8 Hz),117.5-117.9 (CH, J_(C-F) 26.8 Hz), 124.1-124.3 (C, J_(C-F) 15.3 Hz),133.2-133.2 (CH, J_(C-F) 4.5 Hz), 133.7-133.8 (CH, J_(C-F) 8.3 Hz),143.5 (CH), 152.5 (CH) and 157.8-161.5 (C, J_(C-F) 254 Hz); HPLC (70%CH₃CN in H₂O) t_(r)=2.630 (99.30%);

LCMS (APCI), m/z 258.24 (⁸¹BrM⁺+H, 100%), 258.24 (⁷⁹BrM⁺+H, 95);

1-(4-Fluoro-biphenyl-3-ylmethyl)-1H-[1,2,4]triazole (TJA01139, STX1841)

C₁₅H₁₂FN₃ MW 253.27

A 10 mL microwave vial was loaded with TJA01132 (0.100 g, 0.391 mmol),phenylboronic acid (0.071 g, 0.586 mmol), potassium carbonate (0.135 g,0.978 mmol), tetrabutylammonium bromide (0.130 g, 0.391 mmol), Pd(OAc)₂(0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMDiscover Microwave. After a run time of 3 min at 120° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method7) eluting the title compoundas a colourless viscous oil (0.079 g, 80%),

R_(f): 0.45 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.44 (2H, s, ArCH₂N), 7.13-7.20 (2H, m, ArH),7.31-7.57 (7H, m, ArH), 7.96 (1H, s, C₂H₂N₃) and 8.17 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 47.4-47.5 (CH₂, J_(C-F) 4.5 Hz), 116.1-116.4(CH, J_(C-F) 21.7 Hz), 122.1-122.4 (C, J_(C-F) 20.4 Hz), 127.1 (CH),127.8 (CH), 129.0 (CH), 129.3-129.3 (CH, J_(C-F) 3.2 Hz), 129.6-129.5(CH, J_(C-F) 8.9 Hz), 138.2 (C), 139.5 (C), 143.3 (CH), 152.4 (CH) and158.4-162.1 (C, J_(C-F) 260 Hz); HPLC (90% CH₃CN in H₂O) t_(r)=2.197(98.14%); LCMS (APCI), m/z 254.33 (M⁺+H, 100%).

4′-Fluoro-3′-[1,2,4]-triazol-1-ylmethyl-biphenyl-4-ol (TJA01140,STX1842)

C₁₅H₁₂FN₃O MW 269.27

A 10 mL microwave vial was loaded with TJA01132 (0.200 g, 0.781 mmol),4-hydroxyphenylboronic acid (0.164 g, 1.17 mmol), potassium carbonate(0.270 g, 1.95 mmol), tetrabutylammonium bromide (0.260 g, 0.781 mmol),Pd(OAc)₂ (0.005-0.006 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method7) eluting the title compoundas a white solid (0.139 g, 66%),

R_(f): 0.40 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.51 (2H, ArCH₂N), 6.82-6.86 (2H, d, J=8.4Hz, AA′BB′), 7.22-7.30 (1H, t, J=8.6 Hz, ArH), 7.40-7.43 (2H, d, J=8.4Hz, AA′BB′), 7.53-7.58 (2H, m, ArH), 7.99 (1H, s, C₂H₂N₃), 8.69 (1H, s,C₂H₂N₃) and 9.63 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 46.8-46.9 (CH₂, J_(C-F) 3.2 Hz),116.3-116.6 (CH, J_(C-F) 21.7 Hz), 123.7-123.9 (C, J_(C-F) 15.9 Hz),128.3 (CH), 128.4 (CH), 128.8-128.9 (CH, J_(C-F) 3.8 Hz), 130.1 (C),137.4 (C), 137.5 (C), 145.0 (CH), 152.3 (CH), 157.8 (C), 157.0-161.6 (C,J_(C-F) 251.7 Hz);

HPLC (90% CH₃CN in H₂O) t_(r)=1.965 (100%);

LCMS (APCI), m/z 270.40 (M⁺+H, 100%);

3′-Hydroxy-3-[1,2,4]-triazol-1-ylmethyl-biphenyl-4-carbonitrile(TJA01141, STX1843)

C₁₆H₁₂N₄O MW 276.29

A 10 mL microwave vial was loaded with TJA01046 (0.200 g, 0.760 mmol),3-hydroxyphenylboronic acid (0.160 g, 1.14 mmol), potassium carbonate(0.263 g, 1.90 mmol), tetrabutylammonium bromide (0.253 g, 0.760 mmol),Pd(OAc)₂ (0.005-0.006 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method7) eluting the title compoundas a white solid (0.184 g, 89%),

mp 182.7-184.3° C.;

R_(f): 0.33 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.68 (2H, s, ArCH₂N), 6.83-6.87 (1H, dd,J=2.5 & 8.2 Hz, ArH), 7.01-7.10 (2H, m, ArH), 7.28-7.34 (1H, t, J=7.9Hz, ArH), 7.68 (1H, s, ArH), 7.76-7.79 (1H, dd, J=1.8 & 8.1 Hz, ArH),7.93-7.96 (1H, d, J=8.2 Hz, ArH), 8.06 (1H, s, C₂H₂N₃), 8.75 (1H, s,C₂H₂N₃) and 9.73 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 51.0 (CH₂), 110.5 (C), 114.2 (CH), 116.5(CH), 117.7 (C), 118.3 (CH), 127.6 (CH), 128.4 (CH), 130.9 (CH), 134.5(CH), 139.8 (C), 140.2 (C), 145.5 (CH), 145.6 (C), 152.7 (CH) and 158.6(C);

HPLC (90% CH₃CN in H₂O) t_(r)=1.963 (100%);

LCMS (APCI), m/z 277.39 (M⁺+H, 100%).

2-(3′-Benzoyl-5-[1,2,4]-triazol-1-ylmethyl-biphenyl-3-yl)-2-methyl-propionitrile(TJA01142, STX1844)

C₂₆H₂₂N₄O MW 406.48

A 10 mL microwave vial was loaded with TJA01037 (0.100 g, 0.328 mmol),4-benzoylphenylboronic acid (0.111 g, 0.492 mmol), potassium carbonate(0.113 g, 0.820 mmol), tetrabutylammonium bromide (0.109 g, 0.328 mmol),Pd(OAc)₂ (0.002-0.003 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Discover Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (30 mL×3) and brine (30 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purified byflash chromatography (20 g column, method7) eluting the title compoundas a colourless viscous oil (0.108 g, 81%),

R_(f): 0.19 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 1.74 (6H, s, ArC(CH₃)₂CN), 5.45 (2H, s,ArCH₂N), 7.38-7.52 (4H, m, ArH), 7.57-7.70 (4H, m, ArH), 7.79-7.89 (4H,m, ArH), 8.00 (1H, s, C₂H₂N₃) and 8.17 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 29.2 (CH₃), 37.4 (C), 53.3 (CH₂), 124.1 (C),124.3 (CH), 124.6 (CH), 126.4 (CH), 127.4 (CH), 128.5 (CH), 130.1 (CH),130.9 (CH), 132.7 (CH), 136.6 (C), 137.1 (C), 137.5 (c), 142.0 (C),143.4 (C), 143.4 (CH), 143.7 (C), 152.6 (CH) and 196.2 (C═O) (twooverlapping signals);

HPLC (90% CH₃CN in H₂O) t_(r)=2.072 (96.88%);

LCMS (APCI), m/z 407.42 (M⁺+H, 100%).

Sulfamic Acid 3′-(1,2,4)triazol-1-ylmethyl-biphenyl-3-yl Ester(TJA01184, STX1848)

C₁₅H₁₄N₄O₃S MW 330.37

Sulfamoyl chloride in toluene (1.24 mL, 0.743 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA01138 (0.040 g, 0.149 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 20 h. The reaction mixture was then poured into distilledH₂O (30 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over MgSO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as a white solid (0.045 g, 92%),

R_(f): 0.20 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 5.50 (2H, s, ArCH₂N), 7.28-7.31 (2H, d,J=5.2 Hz, ArH), 7.48-7.63 (6H, m, ArH), 8.00 (3H, bs, ArOSO₂NH₂ &C₂H₂N₃), and 8.79 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.6 (CH₂), 121.1 (CH), 122.0 (CH), 125.5(CH), 127.0 (CH), 128.1 (CH), 130.0 (CH), 131.0 (CH), 137.4 (C), 140.0(C), 142.1 (C), 144.9 (CH), 151.2 (C) and 152.4 (CH) (one overlappingsignal);

HPLC (90% CH₃CN in H₂O) t_(r)=1.869 (100%);

LCMS (APCI), m/z 331.42 (M⁺+H, 100%), 252.38 ((M⁺+H)—SO₂NH₂, 20).

HRMS (ES⁺) calcd. for C₁₅H₁₄N₄O₃S (M+H)⁺331.0859, found 331.0857.

3-Chloro-4-hydroxyphenylboronic Acid (TJA01187)

C₆H₆C103 MW 172.37

A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g,24.1 mmol) and purged with N_(2 (g)). Anhydrous THF (100 mL) added withstirring and the vessel cooled to −78° C. (dry ice/acetone bath). After30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was addeddropwise over 20 min. The reaction was left to stir for 1 h.Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with thereaction still at −78° C. After 15 min of stirring at this temperaturethe dry ice/acetone bath was removed. At about 0° C. 2 M HCl_((aq)) (5mL) was added and the reaction left to stir for a further 15 min. THFremoved under vacuum and residues taken up in ethyl acetate (50 mL).Distilled H₂O (50 mL) was added and the organic layer separated. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The organicportions were combined and washed with sat. Na₂CO_(3 (aq)). The aqueouslayer was separated and treated with 2M HCl _((aq)) until the pH wasabout 4. This was then extracted with ethyl acetate (50 mL×2). Theorganic portions were then dried over MgSO₄ and solvent removed. Theresultant off white residues were taken up in a minimum of ethyl acetate(2-3 mL) and added to dropwise to hexane (50 mL) with stirring. Thewhite ppt was filtered to give the title compound as an off white solid(0.490 g, 12%).

¹H NMR (600 MHz, DMSO-d₆) δ 6.89-6.92 (1H, d, J=8.2 Hz, ArH), 7.52-7.56(1H, dd, J=1.8 & 7.9 Hz, ArH), 7.72-7.73 (1H, d, J=1.5 Hz, ArH), 7.98(2H, s, ArB(OH)₂) and 10.33 (1H, s, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.654 (97.92%);

LCMS (APCI), m/z 173.11 (³⁷ClM⁻—H, 15%), 171.10 (³⁵ClM⁻—H, 55), 129.05((³⁷ClM⁻—H)— B(OH)₂, 30), 127.04 ((³⁵ClM⁻—H)— B(OH)₂, 100).

3′-(1,2,4)Triazole-1-yl-methyl-biphenyl-3-chloro-4-ol (TJA01191)

C₁₅H₁₂ClN₃O MW 285.73

A 10 mL microwave vial was loaded with TJA01009 (0.150 g, 0.630 mmol),TJA01187 (0.130 g, 0.756 mmol), potassium carbonate (0.218 g, 1.58mmol), tetrabutylammonium bromide (0.209 g, 0.630 mmol), Pd(OAc)₂(0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 3 min at 120° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (25 mL×3) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) eluted the titlecompound as an off white solid (0.129 g, 72%),

R_(f): 0.35 (ethyl acetate).

¹H NMR (270 MHz, DMSO-d₆) δ 5.46 (2H, s, ArCH₂N), 7.04-7.07 (1H, d,J=8.4 Hz, ArH), 7.18-7.20 (1H, d, J=7.4 Hz, ArH), 7.28-7.62 (5H, m,ArH), 8.01 (1H, s, C₂H₂N₃), 8.71 (1H, s, C₂H₂N₃) and 10.40 (1H, bs,ArOH); HPLC (70% CH₃CN in H₂O) t_(r)=4.274 (96.66%); LCMS (APCI), m/z286.33 (³⁷ClM⁻—H, 30%), 284.32 (³⁵ClM⁻—H, 100).

Sulfamic Acid 3′-(1,2,4)triazol-1-ylmethyl-biphenyl-3-chloro-4-yl Ester(TJA02001, STX1854)

C₁₅H₁₃ClN₄O₃S MW 364.81

Sulfamoyl chloride in toluene (2.03 mL, 1.22 mL) was transferred to a 10mL r.b. flask and the solvent removed under vacuum at 30° C. On coolinga white solid formed to which was added N,N-dimethylacetamide (1.5 mL)to form a colourless solution. TJA01191 (0.070 g, 0.244 mmol) was addedand the solution left to stir at room temperature under N_(2 (g)) for 72h. The reaction mixture was then poured into distilled H₂O (30 mL) andextracted with ethyl acetate (25 mL×2). The organic layers were combinedand washed with distilled H₂O (25 mL×4) and brine (25 mL). Dried overMgSO₄ and solvent removed in vacuo to leave off white residues. Columnchromatography (dichloromethane/acetone 80:20) eluted the title compoundas a white solid (0.055 g, 62%),

Following the same procedure used for TJA01047, TJA02001 was preparedfrom TJA01191 (0.070 g, 0.244 mmol) and sulfamoyl chloride (2.03 mL,1.22 mmol) after 72 h. Purification via column chromatography(dichloromethane/acetone 80:20) eluted the title compound as a whitesolid (0.055 g, 62%),

mp 148.3-153.3° C.;

R_(f): 0.18 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 5.49 (2H, s, ArCH₂N), 7.27-7.31 (1H, d,J=7.4 Hz, ArH), 7.44-7.50 (1H, t, J=5.9 Hz, ArH), 7.57-7.72 (4H, m,ArH), 7.86-7.87 (1H, d, 2.0 Hz), 8.00 (1H, s, C₂H₂N₃), 8.34 (2H, bs,ArOSO₂NH₂) and 8.72 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.5 (CH₂), 124.8 (CH), 127.0 (CH), 127.1(CH), 127.6 (C), 128.2 (CH), 129.0 (CH), 130.0 (CH), 137.7 (C), 138.7(C), 139.9 (C), 144.9 (CH), 146.1 (C) and 152.4 (CH) (one overlappingsignal); HPLC (70% CH₃CN in H₂O) t_(r)=2.694 (100%); LCMS (APCI), m/z367.25 (³⁷ClM⁺+H, 20%), 365.24 (³⁵ClM⁺+H, 55%), 288.22((³⁷ClM⁺+H)—SO₂NH₂, 30%), 286.20 ((³⁵ClM⁺+H)—SO₂NH₂, 100);

HRMS (ES⁺) calcd. for C₁₅H₁₃ClN₄O₃S (M+H)⁺365.0470, found 365.0471.

1-(4-Bromobenzyl)-1H-1,2,4-triazole (TJA02018)

C₉H₈BrN₃ MW 238.08

4-Bromobenzylbromide (5.00 g, 20.0 mmol), 1,2,4-triazole (2.07 g, 30.0mmol), potassium carbonate (2.76 g, 20.0 mmol), potassium iodide (0.190g, 1.18 mmol) and acetone (100 mL) were loaded to an r.b. flask. Withvigorous stirring this mixture was set to reflux (60° C.) for 24 h. Thereaction mixture was allowed to cool and acetone was removed in vacuo.The residues were taken up in ethyl acetate (50 mL) and washed withdistilled water (50 mL×2) and brine (50 mL). Dried over MgSO₄ andsolvent removed in vacuo to leave a yellow solid. Column chromatography(ethyl acetate) eluted the title compound as a white solid (3.24 g,68%),

R_(f): 0.50 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.29 (2H, s, ArCH₂N), 7.10-7.13 (2H, d, J=8.7Hz, AA′BB′), 7.47-7.50 (2H, d, J=8.6 Hz, AA′BB′), 7.96 (1H, s, C₂H₂N₃)and 8.06 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 52.9 (CH₂), 122.9 (C), 129.7 (CH), 132.3(CH), 133.7 (C), 143.2 (CH) and 152.5 (CH); HPLC (90% CH₃CN in H₂O)t_(r)=2.693 (100%); LCMS (APCI), m/z 239.95 (⁸¹BrM⁺+H, 95%), 237.95(⁷⁹BrM⁺+H, 100).

1-Biphenyl-4-methyl-1H-(1,2,4)-triazole (TJA02025, STX1975)

C₁₅H₁₃N₃ MW 235.28

A 10 mL microwave vial was loaded with TJA02018 (0.150 g, 0.630 mmol),phenylboronic acid (0.115 g, 0.945 mmol), potassium carbonate (0.218 g,1.58 mmol), tetrabutylammonium bromide (0.209 g, 0.630 mmol), Pd(OAc)₂(0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave (150 W, 3 min, 120° C.). The reaction mixture wasallowed to cool and ethyl acetate (50 mL) added. This was then washedwith distilled water (25 mL×3) and brine (25 mL). The organic layer wasdried over MgSO₄, filtered and solvent removed in vacuo to leave ayellow/brown residue. Flash chromatography (20 g column, method4) elutedthe title compound as a white solid (0.130 g, 88%),

mp 160.4-164.2° C.;

R_(f): 0.44 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.37 (2H, s, ArCH₂N), 7.31-7.47 (5H, m, ArH),7.54-7.61 (4H, m, ArH), 7.99 (1H, s, C₂H₂N₃) and 8.10 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.4 (CH₂), 127.2 (CH), 127.8 (CH), 127.9(CH), 128.6 (CH), 129.0 (CH), 133.5 (C), 140.4 (C), 141.8 (C), 143.2(CH) and 152.4 (CH); HPLC (90% CH₃CN in H₂O) t_(r)=2.414 (99.30%); LCMS(APCI), m/z 236.06 (M⁺+H, 100%);

4′-(1,2,4)Triazole-1-yl-methyl-biphenyl-4-ol (TJA02026)

C₁₅H₁₃N₃O MW 251.28

A 10 mL microwave vial was loaded with TJA02018 (0.200 g, 0.840 mmol),4-hydroxyphenylboronic acid (0.174 g, 1.26 mmol), potassium carbonate(0.290 g, 2.10 mmol), tetrabutylammonium bromide (0.279 g, 0.840 mmol),Pd(OAc)₂ (0.005-0.006 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Explorer Microwave. After a run time of 3 min at 120° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (25 mL×3) and brine (25 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) eluted the titlecompound as an off white solid (0.151 g, 72%),

R_(f): 0.37 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.42 (2H, s, ArCH₂N), 6.82-6.85 (2H, d,J=8.6 Hz, AA′BB′), 7.32-7.29 (2H, d, J=8.2 Hz, AA′BB′), 7.45-7.48 (2H,d, J=8.6 Hz, AA′BB′), 7.54-7.57 (2H, d, J=8.2 Hz, AA′BB′), 7.99 (1H, s,C₂H₂N₃), 8.68 (1H, s, C₂H₂N₃) and 9.58 (1H, bs, ArOH);

HPLC (90% CH₃CN in H₂O) t_(r)=2.163 (92.21%);

LCMS (APCI), m/z 252.25 (M⁺+H, 100%).

Sulfamic Acid 4′-(1,2,4)triazol-1-ylmethyl-biphenyl-4-yl Ester(TJA02029, STX1976)

C₁₅H₁₄N₄O₃S MW 330.37

Sulfamoyl chloride in toluene (0.30 M, 9.50 mL) was transferred to a 10mL r.b. flask and the solvent removed under vacuum at 30° C. On coolinga white solid formed to which was added N,N-dimethylacetamide (1.5 mL)to form a colourless solution. TJA02026 (0.143 g, 0.570 mmol) was addedand the solution left to stir at room temperature under N_(2 (g)) for 72h. The reaction mixture was then poured into distilled H₂O (30 mL) andextracted with ethyl acetate (25 mL×2). The organic layers were combinedand washed with distilled H₂O (25 mL×4) and brine (25 mL). Dried overMgSO₄ and solvent removed in vacuo to leave off white residues. Columnchromatography (dichloromethane/acetone 80:20) eluted the title compoundas a white solid (0.085 g, 45%),

mp 169.6-175.0° C.;

R_(f): 0.28 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 5.47 (2H, s, ArCH₂N), 7.35-7.39 (4H, dd,J=7.4 & 8.2 Hz, AA′BB′), 7.65-7.76 (4H, dd, J=7.9 & 8.4 Hz, AA′BB′),8.01 (1H, s, C₂H₂N₃), 8.07 (2H, bs, ArOSO₂NH₂) and 8.77 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.3 (CH₂), 123.3 (CH), 127.6 (CH), 128.6(CH), 129.1 (CH), 136.3 (C), 138.6 (C), 139.3 (C), 144.9 (CH), 150.3 (C)and 152.4 (CH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.000 (99.36%);

LCMS (APCI), m/z 331.05 (M⁺+H, 100%);

HRMS (FAB⁺) calcd. for C₁₅H₁₄N₄O₃S (M+H)⁺331.0859, found 331.0858.

2-Bromo-4-methylbenzamide (TJA02017)

C₈H₈BrNO MW 214.06

2-bromo-4-methylbenzoic acid (5.00 g, 23.3 mmol) and thionyl chloride(30 mL) were loaded to a 100 mL r.b. flask and the mixture set to refluxfor 20 h. The reaction was then allowed to cool and excess thionylchloride was removed via a rotary evaporator. Resultant dark brownresidues were taken up in THF (40 mL) and added, with stirring, toammonia water (35%, 50 mL) which had been cooled to 0° C. Left to stirfor 1 h. Conc. HCl_((aq)) was carefully added dropwise until the mixturehad reached pH 3-5. THF was removed via a rotary evaporator and thesolids were filtered and washed thoroughly with distilled H₂O. Afterdrying under vacuum at 70° C. the title compound was obtained as a whitesolid (4.24 g, 84%),

mp 173.2-175.8° C.;

¹H NMR (270 MHz, DMSO-d₆) δ 2.35 (3H, s, ArCH₃), 7.20-7.23 (1H, d, J=8.2Hz, ArH), 7.28-7.31 (1H, d, J=7.7 Hz, ArH), 7.47 (1H, s, ArH), 7.51 (1H,bs, ArCONH₂) and 7.79 (1H, bs, ArCONH₂);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 20.9 (CH₃), 119.1 (C), 128.6 (CH), 129.0(CH), 133.5 (CH), 136.9 (C), 141.3 (C) and 169.6 (C═O);

HPLC (70% CH₃CN in H₂O) t_(r)=4.446 (100%); LCMS (APCI), m/z 215.95(⁸¹BrM⁺+H, 95%), 213.95 (⁷⁹BrM⁺+H, 100).

2-Bromo-4-methylbenzonitrile (TJA02020)

C₈H₆BrN MW 196.04

Phosphorus oxychloride (22.6 mL, 243 mmol), TJA02017 (4.00 g, 18.7 mmol)and sodium chloride (2.40 g, 41.1 mmol) were loaded to a 100 mL r.b.flask and set to reflux with stirring for 4 h. The mixture was allowedto cool and excess phosphorus oxychloride was removed via a rotaryevaporator. The resultant brown residues were poured into iced waterwith stirring and left for 10 min. A brown ppt. had formed and wascollected via filtration, washed thoroughly with distilled H₂O and driedunder vacuum at 70° C. Recrystallisation (hexane) yielded the titlecompound as a white crystalline solid (3.07 g, 84%),

mp 49.9-51.9° C.;

¹H NMR (270 MHz, CDCl₃) δ 2.40 (3H, s, ArH), 7.18-7.22 (1H, d, J=8.6 Hz,ArH) and 7.49-7.54 (2H, m, ArH);

¹³C NMR (67.9 MHz, CDCl₃) δ 21.7 (CH₃), 112.8 (C), 117.5 (C), 125.2 (C),128.6 (CH), 133.8 (CH), 134.1 (CH) and 145.5 (C);

HPLC (70% CH₃CN in H₂O) t_(r)=4.917 (99.75%);

LCMS (APCI), m/z 198.07 (⁸¹BrM⁺+H, 100%), 196.07 (⁷⁹BrM⁺+H, 98%).

2-Bromo-4-(bromomethyl)benzonitrile (TJA02023)

C₈H₅Br₂N MW 274.94

TJA02020 (2.50 g, 12.8 mmol), N-bromosuccinimde (2.73 g, 14.4 mmol),benzyl peroxide (0.100 g, 0.410 mmol) and carbon tetrachloride (50 mL)were loaded to a 100 mL r.b. flask and set to reflux with stirring for 4h. Allowed to cool. The succinimide was filtered off and carbontetrachloride removed via a dry ice-acetone cooled rotary evaporator.The residues were dissolved in dichloromethane (50 mL) and washed withdistilled H₂O (50 mL×3) and brine (50 mL×2). Dried over MgSO₄ andsolvent removed in vacuo to leave yellow residues. Column chromatography(hexane/dichloromethane 60:40) eluted the title compound as a whitecrystalline solid (3.31 g, 94%) of which (by HPLC) 23.39% is TJA02020and 1.32% is 2-bromo-4-(dibromomethyl)benzonitrile.

HPLC (70% CH₃CN in H₂O) t_(r)=4.150 (75.29%);

LCMS (APCI), m/z 276.06 (M⁺+H, 40%).

4-((1H-1,2,4-triazol-1-yl)methyl)-2-bromobenzonitrile (TJA02024,STX1974)

C₁₀H₇BrN₄ MW 263.09

TJA02023 (3.31 g, 12.0 mmol), 1,2,4-triazole (1.24 g, 18.0 mmol),potassium carbonate (1.66 g, 12.0 mmol), potassium iodide (0.117 g,0.706 mmol) and acetone (50 mL) were loaded to an r.b. flask. Withvigorous stirring this mixture was set to reflux (60° C.) for 24 h. Thereaction mixture was allowed to cool and acetone was removed in vacuo.The residues were taken up in ethyl acetate (50 mL) and washed withdistilled water (50 mL×2) and brine (50 mL). Dried over MgSO₄ andsolvent removed in vacuo to leave yellow residues. Column chromatography(ethyl acetate) eluted the title compound as a light yellow solid (1.44g, 56%),

mp 95.7-97.6° C.;

R_(f) 0.30 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.38 (2H, s, ArCH₂N), 7.23-7.27 (1H, dd, J=1.7& 8.2 Hz, ArH), 7.53-7.54 (1H, d, J=1.2 Hz, ArH), 7.63-7.66 (1H, d,J=7.9 Hz, ArH), 8.01 (1H, s, C₂H₂N₃) and 8.17 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 52.1 (CH₂), 115.9 (C), 116.8 (C), 126.1 (C),126.9 (CH), 132.2 (CH), 134.8 (CH), 141.5 (C), 143.7 (CH) and 153.0(CH);

HPLC (70%) R_(t) 2.425 (100%);

LCMS (APCI), m/z 265.15 (⁸¹BrM⁺+H, 95%), 263.15 (⁷⁹BrM⁺+H, 100).

3-[1,2,4]Triazol-1-ylmethyl-biphenyl-6-carbonitrile (TJA02033, STX1978)

C₁₆H₁₂N₄ MW 260.30

A 10 mL microwave vial was loaded with TJA02024 (0.150 g, 0.570 mmol),phenylboronic acid (0.104 g, 0.855 mmol), potassium carbonate (0.198 g,1.43 mmol), tetrabutylammonium bromide (0.189 g, 0.570 mmol), Pd(OAc)₂(0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave (150 W, 3 min, 120° C.). The reaction mixture wasallowed to cool and ethyl acetate (50 mL) added. This was then washedwith distilled water (25 mL×3) and brine (25 mL). The organic layer wasdried over MgSO₄, filtered and solvent removed in vacuo to leave ayellow/brown residue. Flash chromatography (20 g column, method4) elutedthe title compound as a white solid (0.118 g, 80%),

mp 119.3-126.8° C.;

R_(f): 0.49 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) 5.40 (2H, s, ArCH₂N), 7.24-7.34 (2H, m, ArH),7.45-7.48 (5H, m, ArH), 7.74-7.77 (1H, d, J=7.9 Hz, ArH), 8.00 (1H, s,C₂H₂N₃) and 8.17 (1H, s, C₂H₂N₃)

¹³C NMR (67.9 MHz, CDCl₃) δ 52.8 (CH₂), 111.6 (C), 118.2 (C), 126.7(CH), 128.8 (CH), 128.9 (CH), 129.2 (CH), 129.3 (CH), 134.5 (CH), 137.4(C), 140.0 (C), 143.6 (CH), 146.7 (C) and 152.8 (CH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.900 (100%);

LCMS (APCI), m/z 261.20 (M⁺+H, 100%);

HRMS (FAB⁺) calcd. for C₁₆H₁₂N₄ (M+H)⁺261.1135, found 261.1134.

Cyanomethyl-trimethyl-phosphonium Iodide (TJA01110)

C₅H₁₁INP MW 243.03

Trimethylphosphine in THF (1M, 20.0 mL, 20.0 mmol) at 0° C. underN_(2 (g)) was diluted with anhydrous toluene (40 mL). Iodoacetonitrile(1.40 mL, 19.4 mmol) was added dropwise with vigorous stirring forming awhite ppt. The mixture was allowed to warm to r.t. and left to stir for40 h. The mixture was filtered and washed with toluene to give a whitesolid which was dried under vacuum. Recrystallisation (acetonitrile)provided the title compound as a white crystalline solid (3.23 g, 66%),

¹H NMR (300 MHz, DMSO-d₆) δ 2.01-2.06 (9H, d, J=15.3 Hz, P(CH₃)₃),4.01-4.07 (2H, d, J=16.4 Hz, PCH₂CN);

³¹P NMR (121.5 MHz, DMSO-d₆) δ 32.9.

3-Chloro-4-methanesulfonyloxy-benzenesulfonic Acid Sodium Salt(TJA01127)

C₇H₆ClNaO₆S₂ MW 308.69

4-hydroxy-3-chlorobenzenesulfonic acid sodium salt (11.53 g, 50.0 mmol)and sodium hydroxide (2.00 g, 50.0 mmol) were dissolved in distilledwater (50 mL) and the solution cooled to 0° C. Methane sulfonyl chloride(4.25 mL, 55.0 mmol) was added dropwise with stirring and the mixturethen allowed to warm to room temp. and left for 2 h. Brine (20 mL) wasadded and the solution left to stand for 1 h with the formation of whitecrystalline solid. The solids were filtered, recrystallised (brine), anddried under vacuum to give the title compound as a white crystallinesolid (9.40 g, 61%),

mp>250° C.;

¹H NMR (300 MHz, DMSO-d₆) δ 3.31 (3H, s, ArOSO₂CH₃), 7.48-7.51 (1H, d,J=8.4 Hz, ArH), 7.59-7.62 (1H, dd, J=2.2 & 8.4 Hz, ArH) and 7.69-7.72(1H, d, J=2.2 Hz, ArH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 39.1 (CH₃), 124.4 (CH), 126.3 (C), 126.5(CH), 128.3 (CH), 145.3 (C) and 148.8 (C).

Methanesulfonic Acid 2-chloro-4-chlorosulfonyl-phenyl Ester (TJA01128)

C₇H₆Cl₂O₅S₂ MW 305.16

Thionyl chloride (30 mL) was cooled to 0° C. Cautiously, with stirring,TJA01127 (8.60 g, 28.0 mmol) was added followed by DMF (0.5 mL). Thereaction mixture was subsequently heated to reflux (79° C.) for 1 h (oruntil evolution of gas has ceased) and then cooled. Thionyl chloride wasremoved in vacuo and the resulting yellow residues were taken up indichloromethane (50 mL) and distilled water (50 mL) carefully added. Theorganic layer was separated and washed with distilled water (50 mL×2)and brine (50 mL), dried over MgSO₄ and solvent removed in vacuo toleave yellow residues. Recystallisation (dichloromethane/hexane) gavethe title compound as a white crystalline solid (7.10 g, 84%),

¹H NMR (300 MHz, CDCl₃) δ 3.37 (3H, s, ArOSO₂CH₃), 7.70-7.73 (1H, d,J=8.8 Hz, ArH), 7.99-8.03 (1H, dd, J=2.4 & 8.8 Hz, ArH) and 8.19-8.20(1H, d, J=2.4 Hz, ArH);

¹³C NMR (67.9 MHz, CDCl₃) δ 39.6 (CH₃), 125.6 (CH), 127.2 (CH), 128.8(C), 129.9 (CH), 143.1 (C) and 149.9 (C); HPLC (90% CH₃CN in H₂O)t_(r)=2.489 (99.62%);

Methanesulfonic Acid 2-chloro-4-mercapto-phenyl Ester (TJA01129)

C₇H₇ClO₃S₂ MW 238.71

A 50 mL r.b. flask was loaded with red phosphorus powder (0.630 g, 20.5mmol), iodine (0.035 g, 0.137 mmol) and acetic acid (7 mL). CautiouslyTJA01128 (2.50 g, 8.19 mmol) was added and the reaction mixture then setto reflux (118° C.) for 2 h. Distilled water (1.5 mL) was added and themixture left to reflux for a further 1 h. Reaction allowed to cool.Chloroform (30 mL) and distilled water (30 mL) were added. The organiclayer was separated and washed with distilled water (30 mL×3) and brine(30 mL). Dried over MgSO₄, filtered and solvent removed in vacuo. Columnchromatography (ethyl acetate/hexane 50:50) eluted the title compound asa colourless viscous oil (1.68 g, 87%),

R_(f): 0.71 (ethyl acetate);

¹H NMR (300 MHz, CDCl₃) δ 3.24 (3H, s, ArOSO₂CH₃), 3.56 (1H, s, ArSH),7.18-7.22 (1H, dd, J=2.3 & 8.5 Hz, ArH), 7.30-7.33 (1H, d, J=8.1 Hz,ArH) and 7.39-7.40 (1H, d, J=2.2 Hz, ArH);

¹³C NMR (67.9 MHz, CDCl₃) δ 38.7 (CH₃), 125.1 (CH), 127.4 (C), 128.9(CH), 130.9 (CH), 132.1 (C) and 143.2 (C);

HPLC (90% CH₃CN in H₂O) t_(r)=1.811 (92.46%);

LCMS (APCI), m/z 239.01 (³⁷ClM⁻—H, 10%), 237.01 (³⁵ClM⁻—H, 30).

Methyl 3-((1H-1,2,4-triazol-1-yl)methyl)benzoate (TJA02008)

C₁₁H₁₁N₃O₂MW 217.22

Methyl 3-(bromobenzyl)benzoate (5.00 g, 21.8 mmol), 1,2,4-triazole (2.26g, 32.7 mmol), potassium carbonate (3.01 g, 21.8 mmol), potassium iodide(0.213 g, 1.28 mmol) and acetone (100 mL) were loaded to an r.b. flask.With vigorous stirring this mixture was set to reflux (60° C.) for 24 h.The reaction mixture was allowed to cool and acetone was removed invacuo. The residues were taken up in ethyl acetate (50 mL) and washedwith distilled water (50 mL×2) and brine (50 mL). Dried over MgSO₄ andsolvent removed in vacuo to leave a yellow oil. Column chromatography(ethyl acetate) eluted the title compound as a yellow viscous oil togive a yellow crystalline solid (3.35 g, 71%),

R_(f) 0.42 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 3.86 (3H, s, ArCO₂CH₃), 5.37 (2H, s, ArCH₂N),7.39-7.44 (2H, m, ArH), 7.93-7.94 (1H, m, ArH), 7.96 (1H, s, C₂H₂N₃),7.97-8.01 (1H, m, ArH), and 8.09 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 52.4 (CH₃), 53.2 (CH₂), 129.1 (CH), 129.3(CH), 129.9 (CH), 131.1 (C), 132.5 (CH), 135.1 (C), 143.2 (CH), 152.5(CH) and 166.5 (C═O);

HPLC (90% CH₃CN in H₂O) t_(r)=2.080 (100%);

LCMS (APCI), m/z 218.42 (M⁺+H, 100%).

(3-(1H-1,2,4-Triazol-1-yl)methyl)phenyl)methanol (TJA02011)

C₁₀H₁₁N₃O MW 189.21

A 25 mL r.b. flask was loaded with TJA02008 (0.500 g, 2.36 mmol) andpolyethylene glycol 400 (6.0 g). The mixture was heated to 80° C. withstirring until a solution had formed. Sodium borahydride (0.261 g, 6.91mmol) was added carefully resulting in evolution of gas. The reactionmixture was stirred vigorously at 80° C. for 16 h. Extremely viscousglue formed that gradually dissolved in dichloromethane (50 mL) withheating (40° C.). This solution was washed with 1M HCl_((aq)) (10 mL)and then carefully neutralised with sodium bicarbonate. Washed withdistilled water (50 mL×4) and brine (50 mL), separated and dried overMgSO₄. Solvent removed in vacuo to leave a viscous yellow oil. Flashchromatography (20 g column, method6) eluted the title compound as acolourless viscous oil (0.101 g, 22%),

R_(f): 0.24 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 2.53 (1H, bs, ArCH₂OH), 4.66 (2H, s, ArCH₂OH),5.30 (2H, s, ArCH₂N), 7.14-7.17 (1H, m, ArH), 7.29-7.37 (2H, m, ArH),7.89 (1H, s, C₂H₂N₃) and 8.00 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.6 (CH₂), 64.7 (CH₂), 126.5 (CH), 127.2(CH), 129.3 (CH), 134.8 (C), 142.2 (C), 143.1 (CH) and 152.2 (CH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.647 (100%);

LCMS (APCI), m/z 189.75 (M⁺+H, 100%).

4-(3-((1H-1,2,4-triazol-1-yl)methyl)benzylthio)-2-chlorophenylMethanesulfonate (TJA02031)

C₁₇H₁₆ClN₃O₃S₂ MW 409.91

A dry 5 mL r.b. flask purged with N_(2 (g)) was loaded with TJA02011(0.100 g, 0.529 mmol), TJA01129 (0.189 g, 0.794 mmol), TJA01110 (0.154,0.635 mmol), diisopropylethylamine (119 pt, 0.687 mmol) andpropionitrile (1.0 mL). The mixture was then set to stir at 93° C. After18 h the reaction was allowed to cool. Dichloromethane (20 mL) anddistilled water (20 mL) were added and the aqueous layer separated andextracted with dichloromethane (20 mL×2). The organic fractions werecombined and washed with brine (20 mL), dried over MgSO₄ and solventremoved in vacuo to leave yellow residues. Column chromatography (ethylacetate) eluted the title compound as a yellow viscous oil (0.105 g,49%),

R_(f): 0.55 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 3.23 (3H, s, ArOSO₂CH₃), 4.07 (2H, s,ArCH₂SAr), 5.30 (2H, s, ArCH₂N), 7.09-7.16 (3H, m, ArH), 7.26-7.34 (4H,m, ArH), 7.98 (1H, s, C₂H₂N₃) and 8.06 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 38.7 (CH₂), 38.9 (CH₃), 53.3 (CH₂), 124.8(CH), 127.2 (CH), 128.3 (CH), 129.2 (CH), 129.3 (CH), 129.6 (CH), 131.4(CH), 135.2 (C), 136.9 (C), 137.6 (C), 143.2 (CH), 143.6 (C) and 152.3(CH) (one overlapping signal);

HPLC (90% CH₃CN in H₂O) t_(r)=2.006 (99.32%);

LCMS (APCI), m/z 412.08 (³⁷ClM⁺+H, 43%), 410.07 (³⁵ClM⁺+H, 100).

4-(3-((1H-1,2,4-Triazol-1-yl)methyl)benzylthio)-2-chlorophenol(TJA02035)

C₁₆H₁₄ClN₃OS MW 331.82

TJA02031 (0.100 g, 0.244 mmol) was dissolved in THF (2.0 mL) andmethanol (2.0 mL) to which 2M NaOH_((aq)) (0.61 mL) was added. Themixture was set to stir at room temp. for 3 h. THF was removed underreduced pressure and the residues taken up in ethyl acetate (20 mL) andwashed with 2M KHSO_(4 (aq)) (20 mL), distilled water (20 mL×2) andbrine (20 mL). The organic layer was then dried over MgSO₄ and solventremoved under reduced pressure to leave a colourless viscous oil. Columnchromatography (dichloromethane/acetone 80:20) eluted the title compoundas a colourless viscous oil (0.065 g, 80%) that crystallised on standingto a white crystalline solid, mp 131.5-134.9° C.;

R_(f): 0.38 (dichloromethane/acetone 80:20);

¹H NMR (270 MHz, DMSO-d₆) δ 4.08 (2H, s, ArCH₂SAr), 5.38 (2H, s,ArCH₂N), 6.84-6.88 (1H, d, J=8.4 Hz, ArH), 7.07-7.29 (6H, m, ArH), 7.20(1H, s, ArH), 7.98 (1H, s, C₂H₂N₃), 8.63 (1H, s, C₂H₂N₃) and 10.36 (1H,s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 39.1 (CH₂), 52.5 (CH₂), 117.6 (CH), 120.5(C), 125.4 (C), 127.1 (CH), 128.7 (CH), 129.0 (CH), 129.2 (CH), 131.7(CH), 132.8 (CH), 136.9 (C), 138.8 (C), 144.8 (CH), 152.3 (CH) and 153.0(C);

HPLC (100% CH₃CN in H₂O) t_(r)=3.561 (94.57%);

LCMS (APCI), m/z 334.26 (³⁷ClM⁺+H, 35%), 332.24 (³⁵ClM⁺+H, 100).

4-(3-((1H-1,2,4-Triazol-1-yl)methyl)benzylthio)-2-chlorophenyl sulfamate(TJA02037, STX1979)

C₁₆H₁₅ClN₄O₃S₂ Mw 410.03

Sulfamoyl chloride in toluene (2.76 mL, 0.829 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02035 (0.055 g, 0.166 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 20 h. The reaction mixture was then poured into distilledH₂O (30 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over Na₂SO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as an off white waxy solid (0.061 g, 90%);

R_(f): 0.45 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 4.22 (2H, s, ArSCH₂Ar), 5.39 (2H, s,ArCH₂N), 7.14-7.17 (1H, m, ArH), 7.28-7.40 (5H, m, ArH), 7.52-7.53 (1H,d, J=2.0 Hz, ArH), 7.98 (1H, s, C₂H₂N₃), 8.29 (2H, bs, ArOSO₂NH₂) and8.64 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 36.7 (CH₂), 52.4 (CH₂), 124.7 (CH), 127.4(CH), 127.6 (C), 128.2 (CH), 128.7 (CH), 129.0 (CH), 129.4 (CH), 129.6(CH), 136.6 (C), 137.2 (C), 138.0 (C), 144.5 (C), 144.8 (CH) and 152.3(CH);

HPLC (100% CH₃CN in H₂O) t_(r)=7.961 (98.96%);

LCMS (APCI), m/z 413.40 (³⁷ClM⁺+H, 35%), 411.39 (³⁵ClM⁺+H, 100).

Methyl 4-((1H-1,2,4-triazol-1-yl)methyl)benzoate (TJA02010)

C₁₁H₁₁N₃O₂ MW 217.22

Methyl 4-(bromobenzyl)benzoate (5.00 g, 21.8 mmol), 1,2,4-triazole (2.26g, 32.7 mmol), potassium carbonate (3.01 g, 21.8 mmol), potassium iodide(0.213 g, 1.28 mmol) and acetone (100 mL) were loaded to an r.b. flask.With vigorous stirring this mixture was set to reflux (60° C.) for 24 h.The reaction mixture was allowed to cool and acetone was removed invacuo. The residues were taken up in ethyl acetate (50 mL) and washedwith distilled water (50 mL×2) and brine (50 mL). Dried over MgSO₄ andsolvent removed in vacuo to leave a yellow solid. Column chromatography(ethyl acetate) eluted the title compound as a light yellow crystallinesolid (2.77 g, 71%),

mp 119.2-120° C.;

R_(f) 0.38 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 3.85 (3H, s, ArCO₂CH₃), 5.39 (2H, s, ArCH₂N),7.26-7.29 (2H, d, J=8.7 Hz, AA′BB′), 7.97 (1H, s, C₂H₂N₃), 8.00-8.03(2H, d, J=8.4 Hz, AA′BB′) and 8.10 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 52.4 (CH₃), 53.1 (CH₂), 127.8 (CH), 130.4(CH), 130.5 (C), 139.6 (C), 143.4 (CH), 152.3 (CH) and 166.3 (C═O); HPLC(90% CH₃CN in H₂O) t_(r)=2.181 (100%);

LCMS (APCI), m/z 218.23 (M⁺+H, 100%).

(4-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)methanol (TJA02013)

C₁₀H₁₁N₃O MW 189.21

A 25 mL r.b. flask was loaded with TJA02010 (0.500 g, 2.36 mmol) andpolyethylene glycol 400 (6.0 g). The mixture was heated to 80° C. withstirring until a solution had formed. Sodium borohydride (0.261 g, 6.91mmol) was added carefully resulting in evolution of gas. The reactionmixture was stirred vigorously at 80° C. for 16 h. An extremely viscousglue formed that gradually dissolved in dichloromethane (50 mL) withheating (40° C.). This solution was washed with 1M HCl_((aq)) (10 mL)and then carefully neutralised with sodium bicarbonate. Washed withdistilled water (50 mL×4) and brine (50 mL), separated and dried overMgSO₄. Solvent removed in vacuo to leave a viscous yellow oil. Flashchromatography (20 g column, method6) eluted the title compound as acolourless viscous oil (0.175 g, 39%),

mp 72.9-74.2° C.;

¹H NMR (270 MHz, CDCl₃) δ 2.26-2.31 (1H, t, J=5.7 Hz, ArCH₂OH),4.67-4.69 (2H, d, J=5.7 Hz, ArCH₂OH), 5.31 (2H, s, ArCH₂N), 7.22-7.25(2H, d, J=7.8 Hz, AA′BB′), 7.35-7.38 (2H, d, J=8.2 Hz, AA′BB′), 7.93(1H, s, C₂H₂N₃) and 8.01 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.4 (CH₂), 64.7 (CH₂), 127.6 (CH), 128.4(CH), 133.8 (C), 141.8 (C), 143.1 (CH) and 152.2 (CH);

HPLC (90% CH₃CN in H₂O) t_(r)=2.971 (100%);

LCMS (APCI), m/z 190.19 (M⁺+H, 100%).

4-(4-((1H-1,2,4-triazol-1-yl)methyl)benzylthio)-2-chlorophenylMethanesulfonate (TJA02032)

C₁₇H₁₆ClN₃O₃S₂ MW 409.91

A dry 5 mL r.b. flask purged with N_(2 (g)) was loaded with TJA02013(0.100 g, 0.529 mmol), TJA01129 (0.189 g, 0.794 mmol), TJA01175 (0.154,0.635 mmol), diisopropylethylamine (119 μL, 0.687 mmol) andpropionitrile (1.0 mL). The mixture was then set to stir at 93° C. After20 h the reaction was allowed to cool. Dichloromethane (20 mL) anddistilled water (20 mL) were added and the aqueous layer separated andextracted with dichloromethane (20 mL×2). The organic fractions werecombined and washed with brine (20 mL), dried over MgSO₄ and solventremoved in vacuo to leave yellow residues. Column chromatography (ethylacetate) eluted the title compound as a yellow viscous oil (0.115 g,53%),

R_(f): 0.58 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 3.21 (3H, s, ArOSO₂CH₃), 4.12 (2H, s,ArCH₂SAr), 5.30 (2H, s, ArCH₂N), 7.14-7.32 (7H, m, ArH), 7.96 (1H, s,C₂H₂N₃) and 8.06 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 38.4 (CH₂), 38.8 (CH₃), 53.3 (CH₂), 124.9(CH), 126.3 (C), 128.4 (CH), 128.9 (CH), 129.6 (CH), 131.0 (CH), 134.1(C), 137.0 (C), 137.1 (C), 143.2 (CH), 143.5 (C) and 152.3 (CH);

HPLC (90% CH₃CN in H₂O) t_(r)=1.986 (97.35%);

LCMS (APCI), m/z 412.27 (³⁷ClM⁺+H, 35%), 410.26 (³⁵ClM⁺+H, 100).

4-(4-((1H-1,2,4-Triazol-1-yl)methyl)benzylthio)-2-chlorophenol(TJA02036)

C₁₆H₁₄ClN₃OS MW 331.82

TJA02032 (0.100 g, 0.244 mmol) was dissolved in THF (2.0 mL) andmethanol (2.0 mL) to which 2M NaOH_((aq)) (0.61 mL) was added. Themixture was set to stir at room temp. for 2 h. THF was removed underreduced pressure and the residues taken up in ethyl acetate (20 mL) andwashed with 2M KHSO_(4 (aq)) (20 mL), distilled water (20 mL×2) andbrine (20 mL). The organic layer was then dried over MgSO₄ and solventremoved under reduced pressure to leave a colourless viscous oil. Columnchromatography (dichloromethane/acetone 80:20) eluted the title compoundas a white solid (0.066 g, 81%),

mp 133.4-135.7° C.;

R_(f): 0.35 (dichloromethane/acetone 80:20);

¹H NMR (270 MHz, DMSO-d₆) δ 4.09 (2H, s, ArCH₂SAr), 5.37 (2H, s,ArCH₂N), 6.85-6.88 (1H, d, J=8.4 Hz, ArH), 7.09-7.13 (1H, dd, J=2.2 &8.4 Hz, ArH), 7.15-7.25 (4H, dd, J=8.2 & 16.8 Hz, AA′BB′), 7.28-7.29(1H, d, J=2.2 Hz, ArH), 7.97 (1H, s, C₂H₂N₃), 8.63 (1H, s, C₂H₂N₃) and10.34 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 39.0 (CH₂), 52.3 (CH₂), 117.6 (CH), 120.5(C), 125.5 (C), 128.4 (CH), 129.6 (CH), 131.6 (CH), 132.7 (CH), 135.6(C), 138.1 (C), 144.8 (CH), 152.3 (CH) and 152.9 (C);

HPLC (100% CH₃CN in H₂O) t_(r)=3.527 (93.93%);

LCMS (APCI), m/z 334.26 (³⁷ClM⁺+H, 35%), 332.31 (³⁵ClM⁺+H, 100).

4-(4-((1H-1,2,4-Triazol-1-yl)methyl)benzylthio)-2-chlorophenyl sulfamate(TJA02039, STX1980)

C₁₆H₁₅Cln₄O₃S₂ Mw 410.03

Sulfamoyl chloride in toluene (3.01 mL, 0.904 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02036 (0.060 g, 0.181 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 20 h. The reaction mixture was then poured into distilledH₂O (30 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over Na₂SO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as an off white waxy solid (0.067 g, 91%);

mp 128.1-132.5° C.;

R_(f): 0.31 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 4.30 (2H, s, ArSCH₂Ar), 5.38 (2H, s,ArCH₂N), 7.20-7.22 (2H, d, J=8.2 Hz, ArH), 7.37 (3H, m, ArH), 7.40 (1H,s, ArH), 7.54 (1H, s, ArH) 7.97 (1H, s, C₂H₂N₃), 8.27 (2H, bs,ArOSO₂NH₂) and 8.65 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 36.3 (CH₂), 52.9 (CH₂), 124.7 (CH), 127.6(C), 128.0 (CH), 128.5 (CH), 129.4 (CH), 129.7 (CH), 135.9 (C), 136.6(C), 137.3 (C), 144.4 (C), 144.8 (CH) and 152.3 (CH);

HPLC (90% CH₃CN in H₂O) t_(r)=3.246 (100%);

LCMS (APCI), m/z 413.15 (³⁷ClM⁺+H, 42%), 411.14 (³⁵ClM⁺+H, 100).

1-(3-(2-Methoxynaphthalen-6-yl)benzyl)-1H-1,2,4-triazole (TJA02040,STX1981)

C₂₀H₁₇N₃O MW 315.37

A 10 mL microwave vial was loaded with TJA01009 (0.150 g, 0.630 mmol),6-methoxy-2-naphthalene (0.153 g, 0.756 mmol), potassium carbonate(0.218 g, 1.58 mmol), tetrabutylammonium bromide (0.209 g, 0.630 mmol),Pd(OAc)₂ (0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Explorer Microwave. After a run time of 5 min at 150° C. thereaction mixture was allowed to cool and ethyl acetate (50 mL) added.This was then washed with distilled water (25 mL×3) and brine (25 mL).The organic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. Flash chromatography (20 gcolumn, method4) eluted the title compound as a white solid (0.051 g,26%),

mp 133.5-134.1° C.;

R_(f): 0.52 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 3.93 (3H, s, ArOCH₃), 5.42 (2H, s, ArCH₂N),7.15-7.24 (3H, m, ArH), 7.44-7.50 (1H, t, J=7.7 Hz, ArH), 7.58-7.69 (3H,m, ArH), 7.76-7.81 (2H, dd, J=5.0 & 8.4 Hz, ArH), 7.92-7.93 (1H, d,J=1.2 Hz, ArH), 8.00 (1H, s, C₂H₂N₃) and 8.12 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, CDCl₃) δ 53.8 (CH₂), 55.4 (CH₃), 105.6 (CH), 119.4(CH), 125.9 (CH), 126.7 (CH) 127.0 (CH), 127.5 (CH), 127.7 (CH), 129.1(C), 129.7 (CH), 129.8 (CH), 134.0 (C), 135.2 (C), 135.5 (C), 142.3 (C),143.2 (CH), 152.4 (CH) and 158.0 (C) (one overlapping signal);

HPLC (90% CH₃CN in H₂O) t_(r)=3.674 (98.77%);

LCMS (APCI), m/z 316.25 (M⁺+H, 100%);

HRMS (FAB⁺) calcd. for C₂₀H₁₇N₃O (M+H)⁺316.1444, found 316.1447.

6-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)naphthalen-2-ol (TJA02059)

C₁₉H₁₅N₃O MW 301.34

A 10 mL microwave vial was loaded with TJA01009 (0.150 g, 0.630 mmol),TJA02057 (0.178 g, 0.945 mmol), potassium carbonate (0.218 g, 1.58mmol), tetrabutylammonium bromide (0.209 g, 0.630 mmol), Pd(OAc)₂(0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 10 min at 150° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (25 mL×3) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) which eluted the titlecompound as a white solid (0.155 g, 82%),

R_(f): 0.51 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.50 (2H, s, ArCH₂N), 7.10-7.14 (2H, m,ArH), 7.23-7.26 (1H, d, J=7.7 Hz, ArH), 7.44-7.50 (1H, t, J=7.7 Hz,ArH), 7.66-7.86 (5H, m, ArH), 8.00 (1H, s, C₂H₂N₃), 8.05 (1H, s, ArH),8.72 (1H, s, C₂H₂N₃) and 9.85 (1H, bs, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.7 (CH₂), 109.0 (CH), 119.7 (CH), 125.7(CH), 125.8 (CH), 126.8 (CH), 126.9 (CH), 127.1 (CH), 127.3 (CH), 128.5(C), 129.9 (CH), 130.4 (CH), 134.4 (C), 134.5 (C), 137.5 (C), 141.2 (C),144.9 (CH), 152.3 (CH) and 156.2 (C);

HPLC (90% CH₃CN in H₂O) t_(r)=3.136 (97.81%);

LCMS (APCI), m/z 300.38 (M⁻-H, 100%).

2-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)naphthalen-6-yl Sulfamate(TJA02060, STX2052)

C₁₉H₁₆N₄O₃S MW 380.42

Sulfamoyl chloride in toluene (5.53 mL, 1.66 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02059 (0.100 g, 0.332 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 18 h. The reaction mixture was then poured into distilledH₂O (30 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over MgSO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as a white solid (0.066 g, 52%),

mp 172.5-177.6° C.;

R_(f): 0.26 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 5.53 (2H, s, ArCH₂N), 7.29-7.31 (1H, d,J=7.4 Hz, ArH), 7.46-7.51 (2H, m, ArH), 7.78-7.91 (4H, dd, J=9.2 & 25.4Hz, ArH), 8.01 (1H, s, C₂H₂N₃), 8.07-8.11 (4H, m, ArH & ArOSO₂NH₂), 8.28(1H, s, ArH) and 8.75 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.7 (CH₂), 119.6 (CH), 122.7 (CH), 125.7(CH), 126.4 (CH), 127.2 (CH), 127.2 (CH), 127.8 (CH), 129.1 (CH), 130.0(CH), 130.7 (CH), 132.2 (C), 133.1 (C), 137.7 (C), 137.8 (C), 140.5 (C),144.9 (CH), 148.5 (C) and 152.4 (CH);

HPLC (90% CH₃CN in H₂O) t_(r)=8.729 (100%);

LCMS (APCI), m/z 379.47 (M⁻-H, 100%).

1-(3-Ethynylbenzyl)-1H-1,2,4-triazole (TJA02055)

C₁₁H₉N₃ MW 183.21

A dry 25 mL r.b. flask fitted with a condenser was purged with N_(2 (g))and loaded with TJA01009 (0.250 g, 1.05 mmol), trimethylsilylacetylene(174 μL, 1.26 mmol), copper iodide (0.006 g, 3 mol %), PdCl₂(PPh₃)₂(0.022 g, 3 mol %), NEt₃ (3 mL) and anhydrous THF (10 mL). The reactionvessel was then evacuated and backfilled with N_(2 (g)) three times. Thereaction was heated to reflux for 20 h then allowed to cool and the THFwas removed under reduced pressure. Residues were dissolved in EtOAc andfiltered through a pad of silica. Solvent was removed under reducedpressure and the yellow residues (HPLC (100% CH₃CN in H₂O) t_(r)=7.161(90.61%);

LCMS (APCI), m/z 256.35 (M⁺+H, 100%)) were dissolved in MeOH (5 mL) andpotassium carbonate (0.174 g, 1.26 mmol) was added and the mixtureturned brown. Stirred at room temperature for 20 h. Solvent removedunder reduced pressure. Dark brown residues dissolved in EtOAc (30 mL)and washed with distilled water (30 mL×2) and brine (30 mL). Dried overMgSO₄ and solvent removed under reduced pressure to give brown residues.Column chromatography (ethyl acetate) eluted the title compound as anorange/red oil (0.171 g, 89%),

R_(f): 0.60 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 3.08 (1H, s, ArCCH), 5.30 (2H, s, ArCH₂N),7.17-7.38 (3H, m, ArH), 7.43-7.46 (1H, d, J=7.7 Hz, ArH), 7.96 (1H, s,C₂H₂N₃) and 8.07 (1H, s, C₂H₂N₃);

HPLC (90% CH₃CN in H₂O) t_(r)=3.796 (87.54%);

LCMS (APCI), m/z 184.02 (M⁺+H, 100%).

4-(2-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)ethynyl)-2-chlorophenol(TJA02058)

C₁₇H₁₂ClN₃O MW 309.75

A dry 10 mL r.b. flask fitted with a condenser was purged with N_(2 (g))and loaded with TJA02055 (0.100 g, 0.546 mmol), 4-bromo-2-chlorophenol(0.136 g, 0.655 mmol), copper iodide (0.003 g, 3 mol %), PdCl₂(PPh₃)₂(0.011 g, 3 mol %), NEt₃ (1 mL) and anhydrous THF (5 mL). The reactionvessel was then evacuated and backfilled with N_(2 (g)) three times. Thereaction was heated to reflux for 22 h then allowed to cool and the THFwas removed under reduced pressure. Residues were dissolved in EtOAc (30mL) and washed with distilled water (30 mL×2) and brine (30 mL). Driedover MgSO₄ and solvent removed under reduced pressure to give brownresidues. Column chromatography (ethyl acetate) eluted the titlecompound as a yellow solid (0.071 g, 42%),

R_(f): 0.55 (ethyl acetate).

¹H NMR (270 MHz, CDCl₃) δ 5.31 (2H, s, ArCH₂N), 6.47 (1H, bs, ArOH),6.96-6.99 (1H, d, J=8.4 Hz, ArH), 7.19-7.69 (6H, m, ArH), 7.99 (1H, s,C₂H₂N₃) and 8.09 (1H, s, C₂H₂N₃); HPLC (90% CH₃CN in H₂O) t_(r)=2.814(95.24%);

LCMS (APCI), m/z 310.33 (³⁷ClM⁻-H, 30%), 308.31 (³⁵ClM⁻—H, 100).

4-(2-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenyl)ethynyl)-2-chlorophenylsulfamate (TJA02065, STX2054)

C₁₇H₁₃ClN₄O₃S MW 388.83

Sulfamoyl chloride in toluene (1.75 mL, 1.05 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02058 (0.065 g, 0.210 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 18 h. The reaction mixture was then poured into distilledH₂O (30 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over MgSO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as a white solid (0.053 g, 64%),

mp 172.5-177.6° C.;

R_(f): 0.36 (dichloromethane/acetone 80:20).

¹H NMR (270 MHz, DMSO-d₆) δ 5.46 (2H, s, ArCH₂N), 7.35-7.61 (6H, m,ArH), 7.84 (1H, s, ArH), 8.02 (1H, s, C₂H₂N₃), 8.41 (2H, bs, ArOSO₂NH₂)and 8.71 (1H, s, C₂H₂N₃);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.1 (CH₂), 88.0 (C), 90.8 (C), 122.0 (C),122.5 (C), 124.6 (CH), 127.4 (C), 129.4 (CH), 129.8 (CH), 131.4 (CH),131.6 (CH), 132.1 (CH), 133.7 (CH), 137.6 (C), 145.0 (CH), 146.9 (C) and152.5 (CH);

HPLC (90% CH₃CN in H₂O) t_(r)=2.802 (97.73%);

LCMS (APCI), m/z 391.18 (³⁷ClM⁺+H, 35%), 389.16 (³⁵ClM⁺+H, 100).

3-Chloro-4-hydroxyphenylboronic Acid (TJA02028)

C₆H₆ClO₃ MW 172.37

A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g,24.1 mmol) and purged with N_(2(g)). Anhydrous THF (100 mL) added withstirring and the vessel cooled to −78° C. (dry ice/acetone bath). After30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was addeddropwise over 20 min. The reaction was left to stir for 1 h.Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with thereaction still at −78° C. After 15 min of stirring at this temperaturethe dry ice/acetone bath was removed. At about 0° C. 2 M HCl_((aq)) (5mL) was added and the reaction left to stir for a further 15 min. THFremoved under vacuum and residues taken up in ethyl acetate (50 mL).Distilled H₂O (50 mL) was added and the organic layer separated. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The organicportions were combined and washed with sat. Na₂CO_(3 (aq)). The aqueouslayer was separated and treated with 2M HCl _((aq)) until the pH wasabout 4. This was then extracted with ethyl acetate (50 mL×2). Theorganic portions were then dried over MgSO₄ and solvent removed. Theresultant brown residues were taken up in a minimum of ethyl acetate(2-3 mL) and added to dropwise to hexane (50 mL) with stirring. Thebrown ppt was filtered to give the title compound as a brown solid (1.11g, 27%).

¹H NMR (270 MHz, DMSO-d₆) δ 6.89-6.92 (1H, d, J=8.2 Hz, ArH), 7.52-7.56(1H, dd, J=1.8 & 7.9 Hz, ArH), 7.72-7.73 (1H, d, J=1.5 Hz, ArH), 7.98(2H, s, ArB(OH)₂) and 10.33 (1H, s, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.447 (96.77%);

LCMS (APCI), m/z 172.86 (³⁷ClM⁻—H, 28%), 171.10 (³⁵ClM⁻—H, 55), 126.78((³⁵ClM⁻-H)— B(OH)₂, 100).

4′-Hydroxy-3′-chloro-3-[1,2,4]-triazol-1-ylmethyl-biphenyl-6-carbonitrile(TJA02038, STX2112)

C₁₆H₁₁ClN₄O MW 310.74

A 10 mL microwave vial was loaded with TJA01024 (0.150 g, 0.570 mmol),TJA02028 (0.147 g, 0.855 mmol), potassium carbonate (0.198 g, 1.43mmol), tetrabutylammonium bromide (0.189 g, 0.570 mmol), Pd(OAc)₂(0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 5 min at 150° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (25 mL×3) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) to give a white solid(0.074 g). Recrystallisation (dichloromethane) gave the title compoundas a white solid (0.026 g, 13%),

mp 186.2-188.9° C.;

R_(f): 0.44 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.56 (2H, s, ArCH₂N), 7.09-7.12 (1H, d,J=8.4 Hz, ArH), 7.33-7.37 (2H, m, ArH), 7.52 (1H, s, ArH), 7.55-7.56(1H, d, J=2.2 Hz, ArH), 7.90-7.92 (1H, d, J=7.9 Hz, ArH), 8.03 (1H, s,C₂H₂N₃), 8.72 (1H, s, C₂H₂N₃) and 10.67 (1H, bs, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.774 (97.17%);

LCMS (APCI), m/z 311.08 (³⁷ClM⁻—H, 30%), 309.13 (³⁵ClM⁻—H, 100).

4′-Hydroxy-3-[1,2,4]triazol-1-ylmethyl-biphenyl-6-carbonitrile(TJA02034, STX2114)

C₁₆H₁₂N₄O MW 276.29

A 10 mL microwave vial was loaded with TJA02024 (0.150 g, 0.570 mmol),4-hydroxyphenylboronic acid (0.118 g, 0.855 mmol), potassium carbonate(0.198 g, 1.43 mmol), tetrabutylammonium bromide (0.189 g, 0.570 mmol),Pd(OAc)₂ (0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilledwater (3.5 mL). The vial was sealed and loaded (with no prior degassing)into a CEM Explorer Microwave (150 W, 3 min, 120° C.). The reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (25 mL×3) and brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. Flash chromatography (20 gcolumn, method4) eluted a white solid (0.102 g, 65%). Precipitation fromMeOH/CHCl₃ gave the title compound as a white solid (0.085 g, 54%).

mp 211.2-212.7° C.;

R_(f): 0.42 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) 5.62 (2H, s, ArCH₂N), 6.88-6.92 (2H, d, J=8.6Hz, AA′BB′), 7.31-7.33 (1 h, d, J=8.2 Hz, ArH), 7.37-7.39 (2H, d, J=8.5Hz, AA′BB′), 7.45 (1H, s, ArH), 7.87-7.90 (1H, d, J=7.9 Hz, ArH), 8.02(1H, s, C₂H₂N₃), 8.17 (1H, s, C₂H₂N₃) and 9.87 (1H, s, ArOH);

¹³C NMR (69.5.5 MHz, DMSO-d₆) δ 52.0 (CH₂), 109.8 (C), 116.1 (CH), 119.2(C), 127.0 (CH), 128.6 (C), 129.6 (CH), 130.5 (CH), 134.8 (CH), 142.4(C), 145.3 (CH), 145.5 (C), 152.6 (CH) and 158.8 (C);

HPLC (90% CH₃CN in H₂O) t_(r)=1.683 (98.59%);

LCMS (APCI), m/z 277.32 (M⁺+H, 100%);

3-Chloro-4-hydroxyphenylboronic Acid (TJA01187)

C₆H₆ClO₃ MW 172.37

A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g,24.1 mmol) and purged with N_(2 (g)). Anhydrous THF (100 mL) added withstirring and the vessel cooled to −78° C. (dry ice/acetone bath). After30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was addeddropwise over 20 min. The reaction was left to stir for 1 h.Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with thereaction still at −78° C. After 15 min of stirring at this temperaturethe dry ice/acetone bath was removed. At about 0° C. 2 M HCl_((aq)) (5mL) was added and the reaction left to stir for a further 15 min. THFremoved under vacuum and residues taken up in ethyl acetate (50 mL).Distilled H₂O (50 mL) was added and the organic layer separated. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The organicportions were combined and washed with sat. Na₂CO_(3 (aq)). The aqueouslayer was separated and treated with 2M HCl _((aq)) until the pH wasabout 4. This was then extracted with ethyl acetate (50 mL×2). Theorganic portions were then dried over MgSO₄ and solvent removed. Theresultant brown residues were taken up in a minimum of ethyl acetate(2-3 mL) and added to dropwise to hexane (50 mL) with stirring. Thebrown ppt was filtered to give the title compound as a brown solid (1.11g, 27%).

¹H NMR (270 MHz, DMSO-d₆) δ 6.89-6.92 (1H, d, J=8.2 Hz, ArH), 7.52-7.56(1H, dd, J=1.8 & 7.9 Hz, ArH), 7.72-7.73 (1H, d, J=1.5 Hz, ArH), 7.98(2H, s, ArB(OH)₂) and 10.33 (1H, s, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.447 (96.77%);

LCMS (APCI), m/z 172.86 (³⁷ClM⁻—H, 28%), 171.10 (³⁵ClM⁻—H, 55), 126.78((³⁵ClM⁺-H)— B(OH)₂, 100).

2-(4′-Hydroxy-3-chloro-5-[1,2,4]triazol-1-ylmethyl-biphenyl-3-yl)-2-methyl-propionitrile(TJA01189)

C₁₉H₁₇ClN₄O MW 352.82

A 10 mL microwave vial was loaded with TJA01037 (0.200 g, 0.656 mmol),TJA01187 (0.136 g, 0.787 mmol), potassium carbonate (0.227 g, 1.64mmol), tetrabutylammonium bromide (0.218 g, 0.656 mmol), Pd(OAc)₂(0.004-0.005 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 5 min at 150° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) to give a white solid(0.074 g). Recrystallisation (dichloromethane) gave the title compoundas a white solid (0.175 g, 75%),

R_(f): 0.19 (ethyl acetate).

¹H NMR (270 MHz, DMSO-d₆) δ 1.72 (6H, s, ArC(CH₃)₂CN), 5.49 (2H, s,ArCH₂N), 7.05-7.08 (1H, d, J=8.4 Hz, ArH), 7.42-7.51 (3H, m, ArH),7.64-7.68 (2H, m, ArH), 8.02 (1H, s, C₂H₂N₃), 8.73 (1H, s, C₂H₂N₃) and10.44 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 28.8 (CH₃), 37.4 (C), 52.5 (CH₂), 117.6(CH), 120.9 (C), 123.1 (CH), 124.1 (CH), 125.1 (CH), 125.9 (CH), 127.1(CH), 128.6 (CH), 131.9 (C), 138.2 (C), 140.5 (C), 143.2 (C), 144.9(CH), 152.4 (CH) and 153.6 (C);

HPLC (90% CH₃CN in H₂O) t_(r)=1.921 (94.06%);

LCMS (APCI), m/z 353.40 (³⁷ClM⁻-H, 35%), 351.39 (³⁵ClM⁻—H, 100).

3-Chloro-4-hydroxyphenylboronic Acid (TJA01185)

C₆H₆BClO₃ MW 172.37

A dry 250 ml r.b. flask was loaded with 4-bromo-2-chlorophenol (5.00 g,24.1 mmol) and purged with N_(2 (g)). Anhydrous THF (100 mL) added withstirring and the vessel cooled to −78° C. (dry ice/acetone bath). After30 mins n-BuLi, 2.3 M in hexanes, (12.9 mL, 28.9 mmol) was addeddropwise over 20 min. The reaction was left to stir for 1 h.Triisopropyl borate (6.65 mL, 28.9 mmol) was added dropwise with thereaction still at −78° C. After 15 min of stirring at this temperaturethe dry ice/acetone bath was removed. At about 0° C. 2 M HCl_((aq)) (5mL) was added and the reaction left to stir for a further 15 min. THFremoved under vacuum and residues taken up in ethyl acetate (50 mL).Distilled H₂O (50 mL) was added and the organic layer separated. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The organicportions were combined and washed with sat. Na₂CO₃ (₄. The aqueous layerwas separated and treated with 2M HCl _((aq)) until the pH was about 4.This was then extracted with ethyl acetate (50 mL×2). The organicportions were then dried over MgSO₄ and solvent removed. The resultantbrown residues were taken up in a minimum of ethyl acetate (2-3 mL) andadded to dropwise to hexane (50 mL) with stirring. The brown ppt wasfiltered to give the title compound as a brown solid (1.11 g, 27%).

¹H NMR (270 MHz, DMSO-d₆) δ 6.89-6.92 (1H, d, J=8.2 Hz, ArH), 7.52-7.56(1H, dd, 1.8 & 7.9 Hz, ArH), 7.72-7.73 (1H, d, J=1.5 Hz, ArH), 7.98 (2H,s, ArB(OH)₂) and 10.33 (1H, s, ArOH);

HPLC (70% CH₃CN in H₂O) t_(r)=3.447 (96.77%);

LCMS (APCI), m/z 172.86 (³⁷ClM⁻—H, 28%), 171.10 (³⁵ClM⁻H, 55), 126.78((35ClM⁺-H)—B(OH)₂, 100).

4′-Hydroxy-3′-chloro-3-[1,2,4]triazol-1-ylmethyl-biphenyl-4-carbonitrile(TJA02027)

C₁₆H₁₁ClN₄O MW 310.74

A 10 mL microwave vial was loaded with TJA01046 (0.150 g, 0.570 mmol),TJA01085 (0.118 g, 0.684 mmol), potassium carbonate (0.197 g, 1.43mmol), tetrabutylammonium bromide (0.189 g, 0.570 mmol), Pd(OAc)₂(0.003-0.004 g, 2-3 mol %), ethanol (1.5 mL) and distilled water (3.5mL). The vial was sealed and loaded (with no prior degassing) into a CEMExplorer Microwave. After a run time of 3 min at 120° C. the reactionmixture was allowed to cool and ethyl acetate (50 mL) added. This wasthen washed with distilled water (30 mL×3) and brine (30 mL). Theorganic layer was dried over MgSO₄, filtered and solvent removed invacuo to leave a yellow/brown residue. The crude product was purifiedvia flash chromatography (20 g column, method4) eluted the titlecompound as a white solid (0.065 g, 37%),

R_(f): 0.44 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 5.67 (2H, s, ArCH₂N), 7.07-7.10 (1H, d,J=8.4 Hz, ArH), 7.52-7.56 (1H, dd, J=2.2 & 8.2 Hz, ArH), 7.74-7.75 (1H,d, J=2.2 Hz, ArH), 7.80-7.83 (2H, m, ArH), 7.89-7.93 (2H, m, ArH &C₂H₂N₃), 8.04 (1H, s, C₂H₂N₃) and 8.73 (1H, s, ArOH);

¹³C NMR (69.5 MHz, DMSO-d₆) δ 51.1 (CH₂), 110.0 (C), 117.7 (CH), 121.2(C), 126.9 (CH), 127.4 (CH), 128.1 (CH), 128.9 (CH), 130.1 (C), 134.5(CH), 140.0 (C), 144.0 (C), 145.4 (CH), 152.6 (CH) and 154.6 (C) (oneoverlapping signal);

HPLC (90% CH₃CN in H₂O) t_(r)=2.073 (98.19%);

LCMS (APCI), m/z 312.66 (³⁷ClM⁺+H, 35%), 310.64 (³⁵ClM⁺+H, 100).

4-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyloxy)phenol (TJA02079)

C₁₆H₁₅N₃O₂ MW 281.31

A 10 mL r.b. flask, purged with N_(2 (g)) was loaded with TJA02078(0.100 g, 0.528 mmol), triphenyl phosphine (0.168 g, 0.634 mmol),hydroquinone (0.581 g, 5.28 mmol) and anhydrous THF (3 mL) and cooled to0° C. With stirring diethylazodicarboxylate (99.8 μL, 0.634 mmol) wasadded dropwise and the reaction mixture left to stir at room temperaturefor 20 h. THF was then removed in vacuo and the resulting residuesdissolved in ethyl acetate (30 mL) and washed with distilled H₂O (30mL×3), brine (30 mL) and dried over MgSO₄. Solvents were removed invacuo. Column chromatography (ethyl acetate) eluted a white solid thatwas recrystallised (ethyl acetate/hexane) to give the title compound asa white crystalline solid (0.051 g, 34%),

mp 167.4-168.9° C.;

R_(f): 0.41 (ethyl acetate);

¹H NMR (270 MHz, DMSO-d₆) δ 4.96 (2H, s, ArCH₂OAr), 5.41 (2H, s,ArCH₂N), 6.64-6.81 (4H, dd, J=8.9 & 30.1 Hz, AA′BB′), 7.25-7.41 (4H, dd,J=7.9 & 34.6 Hz, AA′BB′), 7.98 (1H, s, C₂H₂N₃), 8.66 (1H, s, C₂H₂N₃) and8.93 (1H, bs, ArOH);

HPLC (90% CH₃CN in H₂O) t_(r)=3.486 (98.68%);

LCMS (APCI), m/z 282.49 (M⁺+H, 70%), 213.32 ((M⁺+H)—C₂H₂N₃, 100%).

4-(4-((1H-1,2,4-Triazol-1-yl)methyl)benzyloxy)phenyl sulfamate (STX2110,TJA02083)

C₁₆H₁₆N₄O₄S MW 360.39

Sulfamoyl chloride in toluene (1.37 mL, 0.889 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02079 (0.050 g, 0.178 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 60 h. The reaction mixture was then poured into distilledH₂O (25 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over MgSO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 80:20)eluted the title compound as a white solid (0.048 g, 75%);

mp 164-166.7° C.

R_(f): 0.32 (dichloromethane/acetone 75:25).

¹H NMR (270 MHz, DMSO-d₆) δ 5.09 (2H, s, ArCH₂OAr), 5.41 (2H, s,ArCH₂N), 7.02-7.19 (4H, dd, J=6.7 & 37.1 Hz, AA′BB′), 7.27-7.45 (4H, dd,J=8.2 & 38.8 Hz, ArH), 7.85 (2H, bs, ArOSO₂NH₂), 7.98 (1H, s, C₂H₂N₃)and 8.67 (1H, s, C₂H₂N₃);

HPLC (70% CH₃CN in H₂O) t_(r)=6.254 (100%);

LCMS (APCI), m/z 361.46 (M⁺+H, 100%).

1-(3-(4-(Benzyloxy)phenoxy)benzyl)-1H-1,2,4-triazole (TJA02081)

C₂₂H₁₉N₃O₂ MW 357.41

A 10 mL r.b. flask was loaded with TJA01009 (0.400 g, 1.68 mmol),4-(benzyloxy)phenol (0.504 g, 2.52 mmol), cesium carbonate (0.888 g,2.52 mmol), (CuOTf)₂.PhH (0.020 g, 5 mol % Cu), ethyl acetate (8 μL, 5mol %), 1-naphthoic acid (0.432 g, 2.52 mmol), 4 Å molecular sieves(0.350 g) and anhydrous tolouene (3.0 mL). The flask was sealed andheated to 110° C. under N_(2 (g)) with stirring for 24 h. The reactionwas then cooled, ethyl acetate (50 mL) added and then washed withdistilled H₂O (30 mL×4), brine (30 mL), dried over MgSO₄ and solventremoved in vacuo to leave brown residues. Column chromatography (ethylacetate) eluted the title compound as an off white solid (0.190 g, 32%),

R_(f): 0.56 (ethyl acetate);

¹H NMR (270 MHz, CDCl₃) δ 5.04 (2H, s, ArCH₂OAr), 5.30 (2H, s, ArCH₂N),6.84-6.96 (7H, m, ArH), 7.24-7.45 (6H, m, ArH), 7.95 (1H, s, C₂H₂N₃) and8.04 (1H, s, C₂H₂N₃);

HPLC (90% CH₃CN in H₂O) t_(r)=5.976 (97.22%);

LCMS (APCI), m/z 358.56 (M⁺+H, 100%).

4-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenoxy)phenol (STX2111, TJA02084)

C₁₅H₁₃N₃O₂ MW 267.28

TJA02081 (0.185 g, 0.518 mmol) was dissolved in THF (2.5 mL) and MeOH(2.5 mL) in an r.b. flask to which was added 5% Pd/C (0.015 g) to form ablack suspension on vigorous stirring. The flask was evacuated and backfilled with H_(2 (g)) via a balloon (×3) and then left to stir for 16 h.The reaction mixture was filtered through celite which was subsequentlywashed with THF (30 mL×2). Solvent was removed in vacuo to leave a brownresidue. Flash chromatography (20 g column, method9) eluted the titlecompound as a white solid (0.112 g, 81%),

mp 156.3-159.7° C.;

R_(f): 0.46 (ethyl acetate), c.f. TJA02081 (0.36);

¹H NMR (270 MHz, DMSO-d₆) δ 5.37 (2H, s, ArCH₂N), 6.74-6.92 (7H, m,ArH), 7.26-7.31 (111, t, J=7.5 Hz, ArH), 7.98 (1H, s, C₂H₂N₂), 8.64 (1H,s, C₂H₂N₂) and 9.39 (1H, s, ArOH);

¹³C NMR (67.9 MHz, DMSO-d₆) δ 52.3 (CH₂), 116.6 (CH), 116.7 (CH), 116.8(CH), 121.7 (CH), 122.0 (CH), 130.6 (CH), 138.8 (C), 144.8 (CH), 147.9(C), 152.3 (CH), 154.6 (C) and 159.2 (C);

HPLC (90% CH₃CN in H₂O) t_(r)=3.294 (97.07%);

LCMS (APCI), m/z 268.44 (M⁺+H, 85%), 199.33 ((M⁺+H)—C₂H₂N₃, 100%).

4-(3-((1H-1,2,4-Triazol-1-yl)methyl)phenoxy)phenyl Sulfamate (STX2113,TJA02086)

C₁₅H₁₄N₄O₄S MW 346.36

Sulfamoyl chloride in toluene (2.17 mL, 1.41 mmol) was transferred to a10 mL r.b. flask and the solvent removed under vacuum at 30° C. Oncooling a white solid formed to which was added N,N-dimethylacetamide(1.5 mL) to form a colourless solution. TJA02084 (0.075 g, 0.281 mmol)was added and the solution left to stir at room temperature underN_(2 (g)) for 70 h. The reaction mixture was then poured into distilledH₂O (25 mL) and extracted with ethyl acetate (25 mL×2). The organiclayers were combined and washed with distilled H₂O (25 mL×4) and brine(25 mL). Dried over MgSO₄ and solvent removed in vacuo to leave offwhite residues. Column chromatography (dichloromethane/acetone 75:25)eluted the title compound as a white solid (0.082 g, 85%);

mp 131.5-133.3° C.

R_(f) 0.23 (dichloromethane/acetone 75:25).

¹H NMR (270 MHz, DMSO-d₆) δ 5.42 (2H, s, ArCH₂N), 6.89-7.05 (3H, m,ArH), 7.07-7.09 (2H, d, J=9.2 Hz, AA′BB′), 7.27-7.29 (2H, d, J=9.2 Hz,AA′BB′), 7.35-7.41 (1H, t, J=7.7 Hz, ArH), 7.99 (3H, s, ArOSO₂NH₂ &C₂H₂N₃) and 8.66 (1H, s, C₂H₂N₃); HPLC (90% CH₃CN in H₂O) t_(r)=3.459(100%); LCMS (APCI), m/z 347.49 (M⁺+H, 100%).

Bromobenzyltriazole intermediate (12) was synthesized by radicalbromination of 3-bromo-5-methylbenzonitrile followed by reacting theresulting 3-bromo-5-(bromomethyl)benzonitrile with 1H-1,2,4-triazole inthe presence of potassium carbonate.

The synthesis of bromobenzyltriazole intermediates 10 and 14 to 15 hasbeen previously disclosed (Jackson 2007 OMC, Jackson 2008 CMC).

Compounds 20 to 58 were produced according to Scheme 1 and theexperimental given in Annex I. The following compounds are also referredto in Annex 1:

-   3-Hydroxy-4-chlorophenylboronic acid (17);-   5-((1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-2-carbonitrile    (19);-   5-((1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-2-carbonitrile    (22);-   3-((1H-1,2,4-triazol-1-yl)methyl)-3′-hydroxybiphenyl-4-carbonitrile    (28);-   3-((1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-4-carbonitrile    (30);-   3-((1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-4-carbonitrile    (32);-   2-(5-((1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-3-yl)-2-methylpropanenitrile    (55); and-   2-(5-((1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-3-yl)-2-methylpropanenitrile    (57).

Biological Data

A number of compounds were tested for aromatase and steroid sulphataseinhibition in accordance with the above Protocols 1 and 6.

JEG3-cells JEG3-cells Aromatase IC₅₀ STS IC₅₀ A: <10 μM A: <10 μMSTRUCTURE B: <1 μM B: <1 μM STX 1361

B NR 1362

A NR 1384

B NR 1385

B NR 1386

B NR 1387

B NR 1388

A NR 1452

B NR 1455

B A 1456

B NR 1457

A NR 1458

B NR 1459

B NR 1502

A NR 1503

B NR 1504

B NR 1505

A NR 1506

B NR 1507

B NR 1508

B NR 1509

B NR 1510

B NR 1511

B NR 1512

B NR 1519

B NR 1520

B NR 1521

B NR 1524

B NR 1525

B NR 1835

B NR 1838

B NR 1839

B NR 1840

B NR 1841

B NR 1842

B NR 1843

B NR 1844

B NR 1848

B A 1854

B B 1975

A NR 1976

A A 1978

B NR 1979

B B 1980

B B 1981

B NR 2052

A NR 2054

NR B Cmpd No.  20

B B  21

B NR  23

B B  24

B NR  25

B NR  26

B NR  29

63.4 ± 2.1% @ 1 μM NR  31

B B  33

B B  34

B NR  35

B NR  36

B NR  37

B NR  38

B NR  39

B NR  40

B A  46

B NR  47

B NR  48

B B  49

B NR  50

B B  51

B NR  52

B NR  53

B NR  56

B NR  58

B 68.2 ± 1.6% @ 10 μM   6

NR NR NR—not recorded

All publications and patents and patent applications mentioned in theabove specification are herein incorporated by reference. Variousmodifications and variations of the present invention will be apparentto those skilled in the art without departing from the scope and spiritof the invention. Although the invention has been described inconnection with specific preferred embodiments, it should be understoodthat the invention as claimed should not be unduly limited to suchspecific embodiments. Indeed, various modifications of the describedmodes for carrying out the invention which are obvious to those skilledin chemistry, biology or related fields are intended to be within thescope of the following claims.

Annex I

5-((1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-2-carbonitrile 19.A 10 mL microwave vial was loaded with 10 (0.150 g, 0.570 mmol),4-hydroxyphenylboronic acid (0.118 g, 0.855 mmol), K₂CO₃ (0.198 g, 1.43mmol), tetrabutylammonium bromide (0.189 g, 0.570 mmol), distilled H₂O(3.5 mL) and EtOH (1.5 mL). The vial was sealed and loaded (with noprior degassing) into a CEM Discover® microwave. After a run time of 5min at 120° C. (150 W) the reaction mixture was allowed to cool anddiluted with EtOAc (50 mL). The resulting mixture was then washed withdistilled H₂O (25 mL×3) and brine (25 mL). The organic layer separatedwas dried (MgSO₄), filtered and solvent removed in vacuo to leave ayellow/brown residue. Column chromatography (EtOAc) eluted 19 as a whitesolid (0.102 g, 65%), mp 211-213° C.; NMR δ_(H) (270 MHz, CDCl₃) 5.62(s, 2H), 6.90 (d, J=8.6, 2H), 7.32 (d, J=8.2, 114), 7.38 (d, J=8.5,214), 7.45 (s, 1H), 7.89 (d, J=7.9, 1H), 8.02 (s, 1H), 8.17 (s, 1H) and9.87 (br s, 1H); LCMS (APCI⁺) m/z (rel intensity) 277 (100, [M+H]⁺);HRMS (ES⁺) M/z calcd. for C₁₆H₁₃N₄O [M+H]⁺: 277.1084, found 277.1084;Anal. (C₁₆H₁₂N₄O) C, H, N.

5′-((1H-1,2,4-triazol-1-yl)methyl)-2′-cyanobiphenyl-4-yl sulfamate 20.As general method using H₂NSO₂Cl (4.63 mL, 1.39 mmol), DMA (1.5 mL) and19 (0.077 g, 0.279 mmol). The reaction mixture was poured into EtOAc (30mL). The organic layer separated was washed with distilled H₂O (30mL×4), brine (30 mL), dried (MgSO₄) and evaporated in vacuo to givewhite residues. Column chromatography (CH₂Cl₂/acetone 80:20) eluted 15as a white solid (0.074 g, 75%), mp 159-162° C.; ¹H NMR δ_(H) (270 MHz,DMSO-d₆) 5.60 (s, 2H), 7.41-7.46 (m, 314), 7.51 (s, 1H), 7.67 (d, J=8.2,2H), 7.98 (d, J=7.9, 1H), 8.03 (s, 1H), 8.17 (br s, 214) and 8.73 (s,1H);

LCMS (APCI⁻) m/z (rel intensity) 354 (100, [M−H]⁻); HRMS (FAB⁺) m/zcalcd. for C₁₆H₁₄N₅O₃S (M+H)⁺: 356.0812, found 356.0811.

5′-((1H-1,2,4-triazol-1-yl)methyl)-2′-cyanobiphenyl-4-yldimethylsulfamate 21. To a white suspension of 19 (0.075 g, 0.271 mmol)and NEt₃ (0.292 mL, 2.71 mmol) in anhydrous CH₂Cl₂ (2 mL) at 0° C. underan inert atmosphere was added to a colourless solution ofN,N-dimethylsulfamoyl chloride (0.408 mL, 3.80 mmol) in anhydrousCH_(A)Cl₂ (3 mL). The resulting white suspension was left to stir underan inert atmosphere at room temperature for 70 h forming a clearorange/brown solution. The reaction mixture was diluted in CH₂Cl₂ (30mL) and washed with distilled H₂O (30 mL×3) and brine (30 mL). Theorganic fraction was separated, dried (MgSO₄), filtered and solventremoved in vacuo to leave yellow residues. Column chromatography(CH₂Cl₂/acetone 75:25) eluted 21 as a viscous yellow oil (0.093 g, 90%);¹H NMR δ_(H) (270 MHz, CDCl₃) 3.00 (s, 6H), 5.44 (s, 2H), 7.28-7.33 (m,2H), 7.39 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H), 7.76 (d, J=7.9 Hz,1H), 8.00 (s, 1H) and 8.18 (s, 1H); LCMS (APCI⁻) m/z (rel intensity) 382(100, [M−H]⁺; HRMS (ES⁺) m/z calcd. for C₁₈H₁₈N₅O₃S [M+H]⁺: 384.1125,found 384.1143.

5′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-2′-cyanobiphenyl-4-ylsulfamate 23. The title compound was prepared from 22 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂Cl₂/acetone 80:20) eluted 23 as a white solid (0.292 g, 93%), mp133-136° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.59 (s, 2H), 7.41-7.46 (d,J=8.2 Hz, 1H), 7.59 (s, 1H), 7.65 (s, 2H), 7.84 (s, 1H), 7.99 (d, J=7.9Hz, 1H), 8.03 (s, 1H), 8.45 (br s, 2H) and 8.72 (s, 1H); LCMS (APCI⁺)m/z (rel intensity) 392 (43, [³⁷CIM+H]⁺), 390 (100, [³⁵CIM+H]⁺); HRMS(FAB⁺) m/z calcd. for C₁₆H₁₃ClN₅O₃S [M+H]⁺: 390.0422, found 390.0421.Anal. (C₁₆H₁₂ClN₅O₃S):

5′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-2′-cyanobiphenyl-4-yldimethylsulfamate 24, The title compound was prepared from 22 usingsimilar conditions to those described for the synthesis of 21.Chromatography (CH₂Cl₂/acetone 75:25) eluted 24 as a white solid (0.189g, 60%), mp 119-120° C.; ¹H NMR δ_(H) (270 MHz, CDCl₃) 3.07 (s, 6H),5.45 (s, 2H), 7.30-7.33 (m, 2H), 7.43 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.58(d, J=2.2 Hz, 1H), 7.62 (d, J=10.9 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.01(s, 1H) and 8.18 (s, 1H); LCMS (APCI), m/z 418 (40, [³⁷CIM+H]⁻), 416(100, [³⁵CIM⁻-H]⁻); HRMS (ES⁺) m/z calcd. for C₁₈H₁₇ClN₅O₃S [M+H]⁺:418.0735, found 418.0725; Anal. (C₁₈H₁₆ClN₅O₃S) C, H, N.

5-(((1H-1,2,4-triazol-1-yl)methyl)-4′-chloro-3′-hydroxybiphenyl-2-carbonitrile25. The title compound was prepared from 10 and 17 using similarconditions to those described for the synthesis of 19. Chromatography(EtOAc) eluted 25 as a white solid (0.111 g, 54%), mp 228-229° C.; ¹HNMR δ_(H) (270 MHz, DMSO-d₆) 5.58 (s, 2H), 6.96 (dd, J=2.2 Hz, 8.2 Hz,1H), 7.11 (d, 2.2 Hz, 1H), 7.41 (dd, J=2.2 Hz, 7.9 Hz, 1H), 7.47 (d,J=8.2 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 8.03 (s,1H), 8.72 (s, 1H) and 10.60 (br s, 1H); LCMS (APCI) m/z (rel intensity)311 (25, [³⁷CIM+H]⁻), 309 (100, [³⁵CIM+H]⁻); HRMS (ES⁺) m/z calcd. forC₁₆H₁₂ClN₄O [M+H]⁺: 311.0694, found 311.0680; Anal. (C₁₆H₁₁ClN₄O) C, H,N.

5′-((1H-1,2,4-triazol-1-yl)methyl)-4-chloro-2′-cyanobiphenyl-3-ylsulfamate 26. The title compound was prepared from 25 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂Cl₂/acetone 80:20) eluted 26 as a white solid (0.087 g, 87%), mp148-150° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.59 (s, 2H), 7.45 (dd,J=1.5 Hz, 7.9 Hz, 1H), 7.57 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.61 (d, J=1.5Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.00 (d, J=7.9Hz, 1H), 8.03 (s, 1H), 8.37 (br s, 2H) and 8.72 (s, 1H); LCMS (APCI) m/z(rel intensity) 390 (20, [³⁷CIM+H]⁻), 388 (100, [³⁵CIM+H]⁻); HRMS (ES⁺)m/z calcd. for C₁₆H₁₃ClN₅O₃S [M+H]⁺: 390.0422, found 390.0421.

3′-((1H-1,2,4-triazol-1-yl)methyl)-4′-cyanobiphenyl-3-yl sulfamate 29.The title compound was prepared from 28 using similar conditions tothose described for the synthesis of 20. Chromatography (CH₂Cl₂/acetone80:20) eluted 29 as a white solid (0.071 g, 92%), mp 137-138° C.; ¹H NMRδ_(H) (270 MHz, DMSO-d₆) 5.69 (s, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.59-7.69(m, 3H), 7.83-7.89 (m, 2H), 8.01-8.03 (m, 2H), 8.09 (s, 2H) and 8.74 (s,1H); LCMS (APCI⁺) m/z (rel intensity) 356 (100, [M+H]⁺); HRMS (ES⁺) m/zcalcd. for C₁₆H₁₄N₅O₃S [M+H]⁺: 356.0812, found 356.0811.

3′-((1H-1,2,4-triazol-1-yl)methyl)-4′-cyanobiphenyl-4-yl sulfamate 31.The title compound was prepared from 30 using similar conditions tothose described for the synthesis of 20. Chromatography (CH₂Cl₂/acetone80:20) eluted 31 as a white solid (0.106 g, 82%), mp 179-180° C.; ¹H NMRδ_(H) (270 MHz, DMSO-d₆) 5.67 (s, 2H), 7.40 (d, J=8.7 Hz, 2H), 7.78 (d,J=8.7 Hz, 2H), 7.82-7.86 (s, 2H), 7.98 (d, J=8.2 Hz, 1H), 8.01 (s, 1H),8.08 (s, 2H) and 8.72 (s, 1H); LCMS (APCI⁺) m/z (rel intensity) 356(100, [M+H]⁺). HRMS (ES⁺) m/z calcd. for C₁₆H₁₄N₅O₃S [M+H]⁺: 356.0812,found 356.0813; Anal. (C₁₆H₁₃N₅O₃S) C, H, N.

3′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-4′-cyanobiphenyl-4-ylsulfamate 33. The title compound was prepared from 32 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂Cl₂/acetone 80:20) eluted 33 as a white solid (0.057 g, 78%), mp155-158° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.73 (s, 2H), 7.62 (d,J=8.7 Hz, 1H), 7.78 (6, J=8.7 Hz, 1H), 7.89-7.98 (m, 4H), 8.01 (s, 1H),8.38 (br s, 2H) and 8.73 (s, 1H); LCMS (APCI⁺) m/z (rel intensity) 392(40, [³⁷CIM+H]⁺), 390 (100, [³⁵CIM+H]⁺); HRMS (ES⁺) m/z calcd. forC₁₆H₁₃ClN₅O₃S [M+H]⁺: 390.0422, found 390.0426.

5-((1H-1,2,4-triazol-1-yl)methyl)biphenyl-3-carbonitrile 34. The titlecompound was prepared from 12 and phenylboronic acid using similarconditions to those described for the synthesis of 19. Chromatography(CHCl₃/acetone 90:10) eluted 34 as a white solid (0.050 g, 77%), mp109-110° C.; ¹H NMR δ_(H) (270 MHz, CDCl₃) 5.45 (s, 2H), 7.44-7.53 (m,6H), 7.67 (s, 1H), 7.84 (s, 1H), 8.03 (s, 1H) and 8.19 (s, 1H); LCMS(ES⁺) m/z (rel intensity) 261 (100, [M+H]⁻); HRMS (ES⁺) m/z calcd. forC₁₆H₁₃N₄ [M+H]⁺: 261.1135, found 261.1122.

5-((1H-1,2,4-triazol-1-yl)methyl)-4′-fluorobiphenyl-3-carbonitrile 35.The title compound was prepared from 12 and 4-fluorophenylboronic acidusing similar conditions to those described for the synthesis of 19.Chromatography (CHCl₃/lacetone 90:10) eluted 35 as a white solid (0.040g, 50%), mp 134-135° C.; ¹H NMR δ_(H) (270 MHz, CDCl₃) 5.45 (s, 2H),7.13-7.21 (m, 2H), 7.46-7.51 (m, 3H), 7.62 (s, 1H), 7.79 (s, 1H), 8.03(s, 1H) and 8.19 (s, 1H); LCMS (ES⁺) m/z (rel intensity) 279 (100,[M+H]⁺); HRMS (ES⁺) m/z calcd. for C₁₆H₁₂FN₄ [M+H]⁺: 279.1041, found279.1030.

5-((1H-1,2,4-triazol-1-yl)methyl)biphenyl-3,4′-dicarbonitrile 36. Thetitle compound was prepared from 12 and 4-cyanophenylboronic acid usingsimilar conditions to those described for the synthesis of 19.Chromatography (CHCl₃/acetone 80:20) eluted 36 as a white solid (0.038g, 47%), mp 154-155° C.; ¹H NMR δ_(H) (270 MHz, CDCl₃) 5.47 (s, 2H),7.49-7.67 (m, 4H), 7.76-7.79 (m, 2H), 7.84 (t, J=1.4 Hz, 1H), 8.03 (s,1H) and 8.21 (s, 1H); LCMS (ES⁺) m/z (rel intensity) 286 (100, [M+H]⁺);HRMS (ES⁺) m/z calcd. for C₁₇H₁₂N₅ [M+H]⁺: 286.1087, found 286.1075.

5-((1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-3-carbonitrile 37.The title compound was prepared from 12 and 4-hydroxyphenylboronic acidusing similar conditions to those described for the synthesis of 19.Chromatography (CHCl₃/acetone 80:20) eluted 37 as a white solid (0.086g, 81%), mp 186-187° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.52 (s, 2H),6.87 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.62 (s, 1H), 7.86 (s,1H), 8.02 (s, 2H), 8.72 (s, 1H) and 9.78 (br s, 1H); LCMS (ES⁻) m/z (relintensity) 277 (100, [M+H]⁻); HRMS (ES⁺) m/z calcd. for C₁₆H₁₃N₄O[M+H]⁺: 277.1084, found 277.1071; Anal. (C₁₆H₁₂N₄O) C, H, N.

3′-((1H-1,2,4-triazol-1-yl)methyl)-5′-cyanobiphenyl-4-yl sulfamate 38.The title compound was prepared from 37 using similar conditions tothose described for the synthesis of 20. Chromatography (CHCl₂/MeOH96:4) eluted 38 as a white solid (0.115 g, 89%), mp 166-167° C.; ¹H NMRδ_(H) (270 MHz, DMSO-₆) 5.56 (s, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.76 (s,1H), 7.81 (d, J=8.5 Hz, 2H), 7.96 (s, 1H), 8.02 (s, 1H), 8.09 (br s,2H), 8.15 (s, 1H) and 8.73 (s, 1H); LCMS (ES⁺) m/z (rel intensity) 356(100, [M H]⁺); HRMS (ES⁺) m/z calcd. for C₁₆H₁₄N₅O₃S [M+H]⁺: 356.0812,found 356.0800.

5-(1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-3-carbonitrile39. The title compound was prepared from 12 and3-chloro-4-hydroxyphenylboronic acid using similar conditions to thosedescribed for the synthesis of 19. Chromatography (CHCl₃/acetone 80:20)eluted 39 as a white solid (0.189 g, 80%), mp 208-209° C.; ¹H NMR Su(270 MHz, DMSO-d₆) 5.52 (s, 2H), 7.06 (d, J=8.5 Hz, 1H), 7.53 (dd, J=2.2and 8.5 Hz, 1H), 7.65 (s, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.95 (s, 1H),8.01 (s, 1H), 8.10 (t, J=1.6 Hz, 1H) and 8.72 (s, 1H); LCMS (ES⁺) m/z(rel intensity) 313 (36, [³⁷CIM+H]⁺), 311 (100, [³⁵CIM+H]⁺); HRMS (ES⁺)m/z calcd. for C₁₆H₁₂ClN₄O [M+H]⁺: 311.0694, found 311.0686; Anal.(C₁₆H₁₁ClN₄O) C, H, N.

3′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-5′-cyanobiphenyl-4-ylsulfamate 40. The title compound was prepared from 39 using similarconditions to those described for the synthesis of 20. Chromatography(CHCl₃/acetone 80:20) eluted 40 as a white solid (0.120 g, 87%), mp163-164° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.55 (s, 2H), 7.61 (d,J=8.8 Hz, 1H), 7.77-7.80 (m, 2H), 8.00-8.04 (m, 3H), 8.22 (s, 1H), 8.36(br s, 2H) and 8.72 (s, 1H); LCMS (ES⁺) m/z (rel intensity) 392 (38,[³⁷CIM+H]⁺), 390 (100, [³⁵CIM+H]⁺), 313 (18, [³⁷CIM-SO₂NH₂]⁺), 311 (56,[³⁵CIM-SO₂NH₂]⁺); HRMS (ES⁺) m/z calcd. for C₁₆H₁₃ClN₅O₃S [M+H]⁺:390.0422, found 390.0408; Anal. (C₁₆H₁₂ClN₅O₃S) C, H. N.

4-(1H-1,2,4-triazol-1-yl)methyl)-4′-hydroxybiphenyl-2-carbonitrile 47.The title compound was prepared from 14 and 4-hydroxyphenylboronic acidusing similar conditions to those described for the synthesis of 19.Chromatography (EtOAc)) eluted 47 as a white solid (0.061 g, 60%), mp168-171° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.51 (s, 2H), 6.89 (d,J=8.7 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.62 (dd,J=2.0 Hz, 8.2 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 8.72 (s,1H) and 9.85 (br s, 1H); LCMS (APCI) m/z (rel intensity) 275 (100, [MH]⁻); HRMS (FAB⁺) calcd. for C₁₆H₁₃N₄O [M+H]⁺: 277.1084, found 277.1077;Anal. (C₁₆H₁₂N₄O)C, H, N.

4′-((1H-1,2,4-triazol-1-yl)methyl)-2′-cyanobiphenyl-4-yl sulfamate 48.The title compound was prepared from 47 using similar conditions tothose described for the synthesis of 20. Chromatography (CH₂Cl₂/acetone80:20) eluted 48 a white solid (0.051 g, 66%), mp 157-160° C.; ¹H NMRδ_(H) (270 MHz, DMSO-d₆) 5.55 (s, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.62-7.70(m, 4H), 7.92 (s, 1H), 8.03 (s, 1H), 8.16 (br s, 2H) and 8.73 (s, 1H);LCMS (APCI⁻) m/z (rel intensity) 354 (100, [M−H]−); HRMS (FAB⁺) calcd.for C₁₆H₁₂ClN₄O₃S [M+H]⁺: 356.0812, found 356.0759.

4-((1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-2-carbonitrile49. The title compound was prepared from 14 and3-chloro-4-hydroxyphenylboronic acid using similar conditions to thosedescribed for the synthesis of 19. Chromatography (EtOAc) eluted 49 as awhite solid (0.072 g, 41%), mp 195-197° C.; ¹H NMR δ_(H) (270 MHz,DMSO-d₆) 5.51 (s, 2H), 7.09 (d, J=8.4 Hz, 1H), 737 (dd, J=2.2 Hz, 8.7Hz, 1H), 7.57-7.61 (m, 3H), 7.86 (s, 1H), 8.02 (s, 1H), 8.72 (s, 1H) and10.68 (br s, 1H); LCMS (APCI⁻) ink (rel intensity) 311 (25, [³⁷CIM+H]⁻),309 (100, [³⁵CIM+H]⁻); HRMS (ES⁺) m/z calcd. for C₁₆H₁₂ClN₄O [M+H]⁺:311.0694, found 311.0681.

4′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-2′-cyanobiphenyl-4-ylsulfamate 50. The title compound was prepared from 49 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂Cl₂/acetone 80:20) eluted 50 as a white solid (0.071 g, 82%), m/z151-153° C.; ¹H NMR 4, (270 MHz, DMSO-d₆) 5.55 (s, 2H), 7.61-7.68 (m,4H), 7.87 (t, J=1.0 Hz, 1H), 7.94 (s, 1H), 8.04 (s, 1H), 8.43 (br s, 2H)and 8.74 (s, 1H); LCMS (APCI⁻) m/z (rel intensity) 391 (20, [³⁷CIM+H]⁻,388 (100, [³⁵CIM+H]⁻); HRMS (ES⁺) m/z calcd. for C₁₆H₁₃ClN₅O₃S [M+H]⁺:390.0422, found 390.0418.

6-((1H-1,2,4-triazol-1-yl)methyl)-3′-chloro-4′-hydroxybiphenyl-3-carbonitrile52. The title compound was prepared from 15 and3-chloro-4-hydroxyphenylboronic acid using similar conditions to thosedescribed for the synthesis of 19. Chromatography (EtOAc) eluted 52 as awhite crystalline solid (0.089 g, 46%), mp 243-245° C.; ¹H NMR δ_(H)(270 MHz, DMSO-d₆) 5.46 (s, 2H), 7.05 (d, J=8.4 Hz, 1H), 7.15-7.23 (m,2H), 7.44 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.80 (dd, J=1.7 Hz,7.9 Hz, 1H), 7.98 (s, 1H), 8.43 (s, 1H) and 10.51 (br s, 1H); LCMS(APCI⁻) m/z (rel intensity) 311 (35, [³⁷CIM+H]⁻), 309 (100, [³⁵CIM+H]⁻);HRMS (ES⁺) m/z calcd. for C₁₆H₁₂ClN₄O [M+H]⁺: 311.0694, found 311.0689.

2′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-5′-cyanobiphenyl-4-ylsulfamate 53. The title compound was prepared from 52 using similarconditions to those described for the synthesis of 15. Chromatography(CH₂Cl₂/acetone 80:20) eluted 53 as a white solid (0.051 g, 82%), mp139-142° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 5.47 (s, 2H), 726 (d, J=7.9Hz, 1H), 7.52 (dd, J=2.2 Hz, 8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.73(d, J=2.2 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.90 (dd, J=1.7 Hz, 7.9 Hz,1H), 7.99 (s, 1H), 8.38 (br s, 2H) and 8.45 (s, 1H); LCMS (APCI⁻) m/z(eel intensity) 390 (20, [³⁷CIM+H]⁻), 388 (60, [³⁵CIM+H]⁻), 311 (35[³⁷CIM-SO₂NH₂]⁻), 309 (100, [³⁵CIM-SO₂NH₂]⁻); HRMS (ES⁺) m/z calcd. forC₁₆H₁₃ClN₅O₃S [M+H]⁺: 390.0422, found 390.0405.

3′-((1H-1,2,4-triazol-1-yl)methyl)-5′-(2-cyanopropan-2-yl)biphenyl-4-ylsulfamate 56. The title compound was prepared from 55 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂Cl₂/acetone 75:25) eluted 56 as a white solid (0.111 g, 86%), mp74-76° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 1.72 (s, 6H), 5.52 (s, 2H),7.37 (d, J=8.7 Hz, 2H), 7.49 (s, 1H), 7.67 (s, 1H), 7.71 (d, J=8.7 Hz,2H), 7.99 (s, 1H), 8.04 (br s, 2H) and 8.71 (s, 1H); LCMS (APCI¹) m/z(rel intensity) 398 (100, [M+H]⁺). HRMS (ES⁺) m/z calcd. for C₁₉H₂₀N₅O₃S[M+H]⁺: 398.1281, found 398.1273.

3′-((1H-1,2,4-triazol-1-yl)methyl)-3-chloro-5′-(2-cyanopropan-2-yl)biphenyl-4-ylsulfamate 58. The title compound was prepared from 57 using similarconditions to those described for the synthesis of 20. Chromatography(CH₂C12/acetone 80:20) eluted 58 as a white solid (0.097 g, 88%), mp71-74° C.; ¹H NMR δ_(H) (270 MHz, DMSO-d₆) 1.74 (s, 6H), 5.53 (s, 2H),7.53 (s, 1H), 7.58-7.61 (m, 2H), 7.71 (d, J=2.2 Hz, 1H), 7.73 (s, 1H),7.94 (d, J=2.2 Hz, 1H), 8.01 (s, 1H)), 8.35 (s, 2H) and 8.74 (s, 1H);LCMS (APCI⁻) m/z (rel intensity) 432 (15, [³⁷CIM+H]⁻), 430 (35,[³⁵CIM+H]⁻), 353 (32, [³⁷CIM-SO2NH2]⁻), 351 (100, [³⁵CIM-SO2NH2]⁻). HRMS(ES⁺) m/z calcd. for C₁₉H₁₉ClN₅O₃S [M+H]⁺: 432.0892, found 432.0889.

The invention is further described by the following numbered paragraphs:

1. A compound of Formula I

-   wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and    —Y—R₈-   wherein each R₈ is independently selected from —OH, hydrocarbyl    groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂), H-bond    acceptors, and halogens;-   wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ in which R₈    is selected from substituted and unsubstituted heterocyclic rings    and amino substituted phenyl groups,-   wherein X is a bond or a linker group-   wherein Y is an optional linker group; and-   wherein ring A is optionally further substituted-   wherein R₉ is selected from H, —OH and —OSO₂NR₁R₂-   wherein R₁ and R₂ are independently selected from H and hydrocarbyl-   wherein    -   (a) X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is        —Y—R₈; OR    -   (b) R₉ is —OSO₂NR₁R₂ or —OH and four of R₃, R₄, R₅, R₆ and R₇        are H and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

2. A compound according to paragraph 1 wherein X is a bond and at leastR₃, R₄, R₅, R₆ and R₇ is —Y—R₈.

3. A compound according to paragraph 2 wherein R₈ is selected from cyano(—CN), halogens and substituted and unsubstituted heterocyclic rings.

4. A compound according to paragraph 2 or 3 wherein R₈ is selected fromcyano (—CN), halogens and ring systems comprising carbon and one, two orthree hetero atoms.

5. A compound according to paragraph 2, 3 or 4 wherein R₈ is selectedfrom cyano (—CN), halogens and ring systems comprising carbon and one ormore hetero atoms selected from Nitrogen, Sulphur and Oxygen.

6. A compound according to any one of paragraphs 2 to 5 wherein R₈ isselected from cyano (—CN), halogens and heterocyclic ring systems,wherein the ring comprises carbon and nitrogen.

7. A compound according to any one of paragraphs 2 to 6 wherein R₈ isselected from cyano (—CN), halogens and ring systems comprising from 3to 10 members.

8. A compound according to any one of paragraphs 2 to 7 wherein R₈ isselected from cyano (—CN), halogens and ring systems comprising from 5,6 or 7 members.

9. A compound according to any one of the preceding paragraphs whereinR₈ is selected from cyano (—CN), halogens and 4H-1,2,4-triazole,1H-1,2,4-triazole and 1H-1,2,3-triazole.

10. A compound according to any one of the preceding paragraphs whereinR₈ is selected from 4H-1,2,4-triazole, 1H-1,2,4-triazole and1H-1,2,3-triazole.

11. A compound according to any one of the preceding paragraphs whereinR₈ is 1H-1,2,4-triazole.

12. A compound according to any one of paragraphs 1 to 9 wherein whenpresent Y is selected from —CH₂— and —C(CH₃)₂—

13. A compound according to any one of paragraphs 1 to 9 wherein —Y—R₈is selected —CH₂-1H-1,2,4-triazole, —CN, —C(CH₃)₂—CN, and —F.

14. A compound according to any one of paragraphs 1 to 9 wherein one—Y—R₈ group is —CH₂-1H-1,2,4-triazole and optionally one further —Y—R₈group selected from —CN, —C(CH₃)₂—CN, and —F.

15. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted heterocyclic rings.

16. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted ring systems comprising carbon andone, two or three hetero atoms.

17. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted ring systems comprising carbon andone or more hetero atoms selected from Nitrogen, Sulphur and Oxygen.

18. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted heterocyclic ring systems, whereinthe ring comprises carbon and nitrogen.

19. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted heterocyclic ring systems comprisingfrom 3 to 10 members.

20. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom substituted and unsubstituted heterocyclic ring systems comprisingfrom 5, 6 or 7 members.

21. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selectedfrom 4H-1,2,4-triazole, 1H-1,2,4-triazole and 1H-1,2,3-triazole.

22. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is1H-1,2,4-triazole.

23. A compound according to any one of the preceding paragraphs whereinat least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein —Y—R₈ is—CH₂-1H-1,2,4-triazole.

24. A compound according to any one of paragraphs 1 to 23 of Formula II

wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ isselected from substituted and unsubstituted heterocyclic rings and aminosubstituted phenyl groups, and at least one of R₃, R₄, R₅, R₆ and R₇ is—Y—R₈ wherein R₈ is selected from cyano (—CN), nitro (—NO₂), H-bondacceptors, and halogens.

25. A compound according to paragraph 24 wherein at least one of R₃, R₄,R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected from substituted andunsubstituted heterocyclic rings and amino substituted phenyl groups,and at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is —CN.

26. A compound according to paragraph 1 wherein R₉ is —OSO₂NR₁R₂ or —OHand four of R₃, R₄, R₅, R₆ and R₇ are H and one of R₃, R₄, R₅, R₆ and R₇is —Y—R₈.

27. A compound according to paragraph 26 wherein R₉ is —OSO₂NR₁R₂ or—OH; wherein R₃, R₄, R₆ and R₇ are H and R₅ is —Y—R₈.

28. A compound according to paragraph 26 wherein R₉ is —OSO₂NR₁R₂ or—OH, wherein R₃, R₅, R₆ and R₇ are H and R₄ is —Y—R₈.

29. A compound according to any one of paragraphs 26 to 28 wherein X isa bond or a linker group selected from —CH₂—S—, —CH₂—O—, —O—, and—CH₂CH₂—.

30. A compound according to any one of paragraphs 26 to 29 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedheterocyclic rings.

31. A compound according to any one of paragraphs 26 to 30 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedring systems comprising carbon and one, two or three hetero atoms.

32. A compound according to any one of paragraphs 26 to 31 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedring systems comprising carbon and one or more hetero atoms selectedfrom Nitrogen, Sulphur and Oxygen.

33. A compound according to any one of paragraphs 26 to 32 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedheterocyclic ring systems, wherein the ring comprises carbon andnitrogen.

34. A compound according to any one of paragraphs 26 to 33 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedheterocyclic ring systems comprising from 3 to 10 members.

35. A compound according to any one of paragraphs 26 to 34 wherein R₈ isselected from cyano (—CN), halogens and substituted and unsubstitutedheterocyclic ring systems comprising from 5, 6 or 7 members.

36. A compound according to any one of paragraphs 26 to 35 wherein R₈ isselected from cyano (—CN), halogens and 4H-1,2,4-triazole,1H-1,2,4-triazole and 1H-1,2,3-triazole.

37. A compound according to any one of paragraphs 26 to 36 wherein R₈ isselected from 4H-1,2,4-triazole, 1H-1,2,4-triazole and1H-1,2,3-triazole.

38. A compound according to any one of paragraphs 26 to 37 wherein —Y—R₈is selected —CH₂-1H-1,2,4-triazole, —CN, —C(CH₃)₂—CN, and —F.

39. A compound according to any one of paragraphs 26 to 38 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted heterocyclic rings.

40. A compound according to any one of paragraphs 26 to 39 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted ring systems comprising carbon and one,two or three hetero atoms.

41. A compound according to any one of paragraphs 26 to 40 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted ring systems comprising carbon and one ormore hetero atoms selected from Nitrogen, Sulphur and Oxygen.

42. A compound according to any one of paragraphs 26 to 41 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted heterocyclic ring systems, wherein thering comprises carbon and nitrogen.

43. A compound according to any one of paragraphs 26 to 42 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted heterocyclic ring systems comprising from3 to 10 members.

44. A compound according to any one of paragraphs 26 to 43 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected fromsubstituted and unsubstituted heterocyclic ring systems comprising from5, 6 or 7 members.

45. A compound according to any one of paragraphs 26 to 44 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is selected from4H-1,2,4-triazole, 1H-1,2,4-triazole and 1H-1,2,3-triazole.

46. A compound according to any one paragraphs 26 to 45 wherein at leastone of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is 1H-1,2,4-triazole.

47. A compound according to any one of paragraphs 26 to 46 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein —Y—R₈ is—CH₂-1H-1,2,4-triazole.

48. A compound according to any one of paragraphs 26 to 47 wherein R₈ is1H-1,2,4-triazole.

49. A compound according to any one of paragraphs 26 to 48 wherein whenpresent Y is selected from —CH₂— and —C(CH₃)₂—

50. A compound according to any one of paragraphs 26 to 49 wherein —Y—R₈is —CH₂-1H-1,2,4-triazole.

51. A compound according to any one of the preceding claim paragraphswherein A is optionally further substituted by groups selected from —OH,hydrocarbyl groups, oxyhydrocarbyl groups, cyano (—CN), nitro (—NO₂),H-bond acceptors, and halogens.

52. A compound according to any one of the preceding paragraphs whereinA is optionally further substituted by groups selected —Cl, —OH, fusedphenyl, phenyl, —OMe, —OCH₂Ph, —CN, —C(O)-Ph, —F, —O-Ph, —C(O)-Me, fusedphenyl optional substituted with one of —OMe or —OH, and a fusedheterocyclic group such that ring A forms a bibezofuranyl.

53. A compound according to any one of the preceding paragraphs whereinA is optionally further substituted by only one or two groups.

54. A compound according to paragraph 1 selected from compounds of theformulae

55. A compound according to any one of paragraphs 1 to 54 for use inmedicine.

56. A pharmaceutical composition comprising the compound according toany one of paragraphs 1 to 54 optionally admixed with a pharmaceuticallyacceptable carrier, diluent, excipient or adjuvant.

57. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for use in the therapy of a condition ordisease associated with STS and/or aromatase and/or cell cycling and/orapoptosis and/or cell growth.

58. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for use in the therapy of a condition ordisease associated with STS and aromatase.

59. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for use in the therapy of a condition ordisease associated with adverse STS levels and/or adverse aromataselevels and/or cell cycling and/or apoptosis and/or cell growth.

60. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for use in the therapy of a condition ordisease associated with adverse STS levels and adverse aromatase levels.

61. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for inhibiting STS activity and/orinhibiting aromatase activity.

62. Use of a compound according to any one of paragraphs 1 to 54 in themanufacture of a medicament for inhibiting STS activity and inhibitingaromatase activity.

63. A compound as substantially hereinbefore described with reference tothe Examples.

64. A composition as substantially hereinbefore described with referenceto the Examples.

65. A method or use as substantially hereinbefore described withreference to the Examples.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

1. A compound of Formula I

wherein R₃, R₄, R₅, R₆ and R₇ are independently selected from H and—Y—R₈ wherein each R₈ is independently selected from cyano (—CN) andsubstituted and unsubstituted 5 membered ring systems comprising carbonand one, two, or three hetero atoms selected from nitrogen, sulphur, andoxygen; wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ in whichR₈ is selected from substituted and unsubstituted heterocyclic rings andamino substituted phenyl groups, wherein X is a bond or a group selectedfrom an alkyl group, an alkenyl group, an alkynl group, an aryl group,an alkoxy group, and oxyalkenyl group, an oxyalkynyl group, and oxyarylgroup, COO, CO, S, O, SO, SO₂, NR, and SO₂NR, wherein R is selected fromH, an alkyl group, an alkenyl group, an alkynyl group and an aryl group;wherein Y is an optional group selected from an alkyl group, an alkenylgroup and an alkynly group; and wherein ring A is optionally furthersubstituted wherein R₉ is —OSO₂NR₁R₂ wherein R₁ and R₂ are H wherein (a)X is a bond and at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈; OR (b)four of R₃, R₄, R₅, R₆ and R₇ are H and one of R₃, R₄, R₅, R₆ and R₇ is—Y—R₈.
 2. A compound according to claim 1 wherein X is a bond and atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.
 3. A compound according toclaim 2 wherein R₈ is selected from cyano (—CN) and substituted andunsubstituted 5 membered ring systems comprising carbon and one, two orthree nitrogens.
 4. A compound according to claim 1 wherein R₈ isselected from cyano (—CN), halogens and 4H-1,2,4-triazole,1H-1,2,4-triazole and 1H-1,2,3-triazole.
 5. A compound according toclaim 1 wherein R₈ is selected from 4H-1,2,4-triazole, 1H-1,2,4-triazoleand 1H-1,2,3-triazole.
 6. A compound according to claim 1 wherein R₈ is1H-1,2,4-triazole.
 7. A compound according to claim 1 wherein whenpresent Y is selected from —CH₂— and —C(CH₃)₂—.
 8. A compound accordingto claim 1 wherein —Y—R₈ is selected —CH₂-1H-1,2,4-triazole, —CN,—C(CH₃)₂—CN, and —F.
 9. A compound according to claim 1 wherein one—Y—R₈ group is —CH₂-1H-1,2,4-triazole and optionally one further —Y—R₈group selected from —CN, —C(CH₃)₂—CN, and —F.
 10. A compound accordingto claim 1 wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈wherein R₈ is selected from 4H-1,2,4-triazole, 1H-1,2,4-triazole and1H-1,2,3-triazole.
 11. A compound according to claim 1 wherein at leastone of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is 1H-1,2,4-triazole.12. A compound according to claim 1 wherein at least one of R₃, R₄, R₅,R₆ and R₇ is —Y—R₈ wherein —Y—R₈ is —CH₂-1H-1,2,4-triazole.
 13. Acompound according to claim 1 of Formula II

wherein at least one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ isselected from substituted and unsubstituted 5 membered ring systemscomprising carbon and one, two or three hetero atoms selected fromnitrogen, sulphur and oxygen, and at least one of R₃, R₄, R₅, R₆ and R₇is —Y—R₈ wherein R₈ is selected from cyano (—CN), and halogens andsubstituted and unsubstituted 5 membered ring systems comprising carbonand one, two or three hetero atoms selected from nitrogen, sulphur andoxygen.
 14. A compound according to claim 13 wherein at least one of R₃,R₄, R₅R₆ and R₇ is —Y—R₈ wherein R₈ is selected from substituted andunsubstituted 5 membered ring systems comprising carbon and one, two orthree hetero atoms selected from nitrogen, sulphur and oxygen, and atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is —CN.
 15. Acompound according to claim 1 wherein four of R₃, R₄, R₅, R₆ and R₇ areH and one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈.
 16. A compound according toclaim 15 wherein R₉ is —OSO₂NR₁R₂, wherein R₃, R₅, R₆ and R₇ are H andR₄ is —Y—R₈.
 17. A compound according to claim 15 wherein R₉ is—OSO₂NR₁R₂ , wherein R₃, R₅, R₆ and R₇ are H and R₄ is —Y—R₈.
 18. Acompound according to claim 15 wherein X is a bond or a group selectedfrom —CH—S—, —C≡C—, —CH₂—O—, —O—, and —CH₂CH₂—.
 19. A compound accordingto claim 15 wherein R₈ is selected from cyano (—CN), halogens and4H-1,2,4-triazole, 1H-1,2,4-triazole and 1H-1,2,3-triazole.
 20. Acompound according to claim 15 wherein R₈ is selected from4H-1,2,4-triazole, 1H-1,2,4-triazole and 1H-1,2,3-triazole.
 21. Acompound according to claims 15 wherein —Y—R₈ is selected—CH₂-1H-1,2,4-triazole, —CN, —C(CH₃)₂—CN, and —F.
 22. A compoundaccording to claim 15 wherein at least one of R₃, R₄, R₅, R₆, and R₇ is—Y—R₈ wherein R₈ s is selected from substituted and unsubstituted 5membered ring systems comprising carbon and one, two or three heteroatoms selected from nitrogen, sulphur and oxygen.
 23. A compoundaccording to claim 15 wherein at least one of R₃, R₄, R₅, R₆ and R₇ is—Y—R₈ wherein R₈ is selected from 4H-1,2,4-triazole, 1H-1,2,4-triazoleand 1H-1,2,3-triazole.
 24. A compound according to claim 15 wherein atleast one of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein R₈ is1H-1,2,4-triazole.
 25. A compound according to claim 15 wherein at leastone of R₃, R₄, R₅, R₆ and R₇ is —Y—R₈ wherein —Y—R₈ is—CH₂-1H-1,2,4-triazole.
 26. A compound according to claim 15 wherein R₈is 1H-1,2,4-triazole.
 27. A compound according to claim 15 wherein whenpresent Y is selected from —CH₂— and —C(CH₃)₂—.
 28. A compound accordingto claim 15 wherein —Y—R₈ is —CH₂-1H-1,2,4-triazole.
 29. A compoundaccording to claim 1 wherein A is optionally further substituted bygroups selected from —OH, optionally substituted linear, branched orcyclic alkyl groups, optionally substituted linear, branched or cyclicalkenyl groups, optionally substituted linear, branched or cyclicalkenyl groups, aryl groups, optionally substituted linear, branched orcyclic alkoxy groups, optionally substituted linear, branched or cyclicoxyalkenyl group optionally substituted linear, branched or cyclic,optionally substituted linear, branched or cyclic oxyalkynyl groups,oxyaryl groups, cyano (—CN), nitro (—NO₂), and halogens.
 30. A compoundaccording to claim 1 wherein A is optionally further substituted by onlyone or two groups.
 31. A compound according to claim 1 selected fromcompounds or the formulae


32. A pharmaceutical composition comprising the compound according toclaim 1 admixed with a pharmaceutically acceptable carrier, diluent,excipient or adjuvant.